bims-proarb 2021-08-22 papers

bims-proarb

Biomed News

on Proteostasis in aging and regenerative biology

Issue of 2021‒08‒22
28 papers selected by
Rich Giadone
Harvard University

Protein misfolding, ER Stress and Chaperones: An approach to develop chaperone-based therapeutics for Alzheimer's Disease.
The unfolded protein response as regulator of cancer stemness and differentiation: mechanisms and implications for cancer therapy.
Doxycycline promotes proteasome fitness in the central nervous system.
The Proteome Folding Problem and Cellular Proteostasis.
Mechanism of Endoplasmic Reticulum Stress in Cerebral Ischemia.
Extracellular Hsp90 and protection of neuronal cells through Nrf2.
DAXX represents a new type of protein-folding enabler.
Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action.
Erythrocytes, a New Contributor to Age-Associated Loss of Blood-Brain Barrier Integrity.
Empirical versus theoretical power and type I error (false-positive) rates estimated from real murine aging research data.
Ubiquitin protein helps cells to recover from stress.
Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation.
Autophagy Promoted Neural Differentiation of Human Placenta-derived Mesenchymal Stem Cells.
Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease.
Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer's Disease.
Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity.
The pancreatic β cell response to secretory demands and adaption to stress.
Planar cell polarity signaling components are a direct target of β-amyloid-associated degeneration of glutamatergic synapses.
Disease modeling for Mucopolysaccharidosis type IIIB using patient derived induced pluripotent stem cells.
Autophagy and Ciliogenesis.
Feedback control of protein aggregation.
Nonhuman primates at the intersection of aging biology, chronic disease, and health: An introduction to the American journal of primatology special issue on aging, cognitive decline, and neuropathology in nonhuman primates.
The killifish visual system as an in vivo model to study brain aging and rejuvenation.
Formaldehyde-crosslinked nontoxic A β monomer to form the toxic A β dimers and aggregates: Pathogenicity and therapeutic perspectives.
Protocol to study starvation-induced autophagy in developing rat neurons.
Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer's disease.
Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration.
A Specialized Nutritional Formulation Prevents Hippocampal Glial Activation and Memory Impairment Induced by Amyloid-β Oligomers in Mice.

Int J Neurosci. 2021 Aug 17. 1-32

Protein misfolding, ER Stress and Chaperones: An approach to develop chaperone-based therapeutics for Alzheimer's Disease.

Rimaljot Singh, Navpreet Kaur, Neelima Dhingra, Tanzeer Kaur.

  Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder with complex etiology that eventually leads to dementia. The main culprit of AD is the extracellular deposition of β-amyloid (Aβ) and intracellular neurofibrillary tangles. The protein conformational change and protein misfolding are the key events of AD pathophysiology, therefore endoplasmic reticulum (ER) stress is an apparent consequence. ER, stress-induced unfolded protein response (UPR) mediators (viz. PERK, IRE1, and ATF6) have been reported widely in the AD brain. Considering these factors, preventing proteins misfolding or aggregation of tau or amyloidogenic proteins appears to be the best approach to halt its pathogenesis. Therefore, therapies through chemical and pharmacological chaperones came to light as an alternative for the treatment of AD. Diverse studies have demonstrated 4-phenylbutyric acid (4-PBA) as a potential therapeutic agent in AD. The current review outlined the mechanism of protein misfolding, different etiological features behind the progression of AD, the significance of ER stress in AD, and the potential therapeutic role of different chaperones to counter AD. The study also highlights the gaps in current knowledge of the chaperones-based therapeutic approach and the possibility of developing chaperones as a potential therapeutic agent for AD treatment.

Keywords:  Alzheimer’s disease; chemical chaperone; unfolded protein response; β-amyloid

DOI:  https://doi.org/10.1080/00207454.2021.1968859
Biochem Pharmacol. 2021 Aug 16. pii: S0006-2952(21)00353-1. [Epub ahead of print] 114737

The unfolded protein response as regulator of cancer stemness and differentiation: mechanisms and implications for cancer therapy.

Dong Liang, Mohammad Khoonkari, Tony Avril, Eric Chevet, Frank A E Kruyt.

  The unfolded protein response (UPR) is an adaptive mechanism that regulates protein and cellular homeostasis. Three endoplasmic reticulum (ER) membrane localized stress sensors, IRE1, PERK and ATF6, coordinate the UPR in order to maintain ER proteostasis and cell survival, or induce cell death when homeostasis cannot be restored. However, recent studies have identified alternative functions for the UPR in developmental biology processes and cell fate decisions under both normal and cancerous conditions. In cancer, increasing evidence points towards the involvement of the three UPR sensors in oncogenic reprogramming and the regulation of tumor cells endowed with stem cell properties, named cancer stem cells (CSCs), that are considered to be the most malignant cells in tumors. Here we review the reported roles and underlying molecular mechanisms of the three UPR sensors in regulating stemness and differentiation, particularly in solid tumor cells, processes that have a major impact on tumor aggressiveness. Mainly PERK and IRE1 branches of the UPR were found to regulate CSCs and tumor development and examples are provided for breast cancer, colon cancer and aggressive brain tumors, glioblastoma. Although the underlying mechanisms and interactions between the different UPR branches in regulating stemness in cancer need to be further elucidated, we propose that PERK and IRE1 targeted therapy could inhibit self-renewal of CSCs or induce differentiation that is predicted to have therapeutic benefit. For this, more specific UPR modulators need to be developed with favorable pharmacological properties that together with patient stratification will allow optimal evaluation in clinical studies.

Keywords:  IRE1; PERK; cancer stem cells; therapy; tumor formation; unfolded protein response

DOI:  https://doi.org/10.1016/j.bcp.2021.114737
Sci Rep. 2021 Aug 20. 11(1): 17003

Doxycycline promotes proteasome fitness in the central nervous system.

Edmund Charles Jenkins, Matthew J O'Connell, Giovanni Manfredi, Doris Germain.

Several studies reported that mitochondrial stress induces cytosolic proteostasis in yeast and C. elegans. Notably, inhibition of mitochondrial translation with doxcycyline decreases the toxicity of β-amyloid aggregates, in a C. elegans. However, how mitochondrial stress activates cytosolic proteostasis remains unclear. Further whether doxycycline has this effect in mammals and in disease relevant tissues also remains unclear. We show here that doxycycline treatment in mice drastically reduces the accumulation of proteins destined for degradation by the proteasome in a CNS region-specific manner. This effect is associated with the activation of the ERα axis of the mitochondrial unfolded protein response (UPRmt), in both males and females. However, sexually dimorphic mechanisms of proteasome activation were observed. Doxycycline also activates the proteasome in fission yeast, where ERα is not expressed. Rather, the ancient ERα-coactivator Mms19 regulates this response in yeast. Our results suggest that the UPRmt initiates a conserved mitochondria-to-cytosol stress signal, resulting in proteasome activation, and that this signal has adapted during evolution, in a sex and tissue specific-manner. Therefore, while our results support the use of doxycycline in the prevention of proteopathic diseases, they also indicate that sex is an important variable to consider in the design of future clinical trials using doxycycline.

DOI: https://doi.org/10.1038/s41598-021-96540-z
J Mol Biol. 2021 Aug 12. pii: S0022-2836(21)00430-7. [Epub ahead of print] 167197

The Proteome Folding Problem and Cellular Proteostasis.

Evan T Powers, Lila M Gierasch.

  Stunning advances have been achieved in addressing the protein folding problem, providing deeper understanding of the mechanisms by which proteins navigate energy landscapes to reach their native states and enabling powerful algorithms to connect sequence to structure. However, the realities of the in vivo protein folding problem remain a challenge to reckon with. Here, we discuss the concept of the "proteome folding problem"-the problem of how organisms build and maintain a functional proteome-by admitting that folding energy landscapes are characterized by many misfolded states and that cells must deploy a network of chaperones and degradation enzymes to minimize deleterious impacts of these off-pathway species. The resulting proteostasis network is an inextricable part of in vivo protein folding and must be understood in detail if we are to solve the proteome folding problem. We discuss how the development of computational models for the proteostasis network's actions and the relationship to the biophysical properties of the proteome has begun to offer new insights and capabilities.

Keywords:  Protein folding; chaperone; computational modeling; energy landscape; proteome folding; proteostasis

DOI:  https://doi.org/10.1016/j.jmb.2021.167197
Front Cell Neurosci. 2021 ;15 704334

Mechanism of Endoplasmic Reticulum Stress in Cerebral Ischemia.

Yu Han, Mei Yuan, Yi-Sha Guo, Xin-Ya Shen, Zhen-Kun Gao, Xia Bi.

  Endoplasmic reticulum (ER) is the main organelle for protein synthesis, trafficking and maintaining intracellular Ca2+ homeostasis. The stress response of ER results from the disruption of ER homeostasis in neurological disorders. Among these disorders, cerebral ischemia is a prevalent reason of death and disability in the world. ER stress stemed from ischemic injury initiates unfolded protein response (UPR) regarded as a protection mechanism. Important, disruption of Ca2+ homeostasis resulted from cytosolic Ca2+ overload and depletion of Ca2+ in the lumen of the ER could be a trigger of ER stress and the misfolded protein synthesis. Brain cells including neurons, glial cells and endothelial cells are involved in the complex pathophysiology of ischemic stroke. This is generally important for protein underfolding, but even more for cytosolic Ca2+ overload. Mild ER stress promotes cells to break away from danger signals and enter the adaptive procedure with the activation of pro-survival mechanism to rescue ischemic injury, while chronic ER stress generally serves as a detrimental role on nerve cells via triggering diverse pro-apoptotic mechanism. What's more, the determination of some proteins in UPR during cerebral ischemia to cell fate may have two diametrically opposed results which involves in a specialized set of inflammatory and apoptotic signaling pathways. A reasonable understanding and exploration of the underlying molecular mechanism related to ER stress and cerebral ischemia is a prerequisite for a major breakthrough in stroke treatment in the future. This review focuses on recent findings of the ER stress as well as the progress research of mechanism in ischemic stroke prognosis provide a new treatment idea for recovery of cerebral ischemia.

Keywords:  Ca2+ homeostasis; ER stress; apoptosis; cerebral ischemia; inflammation; unfolded protein response

DOI:  https://doi.org/10.3389/fncel.2021.704334
Biochem Soc Trans. 2021 Aug 20. pii: BST20210370. [Epub ahead of print]

Extracellular Hsp90 and protection of neuronal cells through Nrf2.

Stuart K Calderwood, Thiago J Borges, Takanori Eguchi, Benjamin J Lang, Ayesha Murshid, Yuka Okusha, Thomas L Prince.

  Heat shock protein 90 (Hsp90), although one of the most essential intracellular chaperones, can also play key roles in the extracellular milieu. Here, we review the properties of extracellular Hsp90 in cellular homeostasis in the heat shock response (HSR), focusing on cells of the central nervous system. Hsp90 can be secreted by microglia as well as other cell types by non-canonical pathways of secretion. The chaperone may then influence the behavior of distant cells and can for instance protect neuronal cells from the oxidative burst accompanying phagocytosis by microglia of beta-amyloid fibrils. A mechanism involving activation of the transcription factor Nrf2, and induction of the antioxidant response is reported. We review the potential role of extracellular Hsp90, Nrf2 and transcellular chaperone signaling in the non-cell-intrinsic HSR.

Keywords:  Nrf2; cytoprotection; extracellular; heat shock proteins

DOI:  https://doi.org/10.1042/BST20210370
Nature. 2021 Aug 18.

DAXX represents a new type of protein-folding enabler.

Liangqian Huang, Trisha Agrawal, Guixin Zhu, Sixiang Yu, Liming Tao, JiaBei Lin, Ronen Marmorstein, James Shorter, Xiaolu Yang.

Protein quality control systems are crucial for cellular function and organismal health. At present, most known protein quality control systems are multicomponent machineries that operate via ATP-regulated interactions with non-native proteins to prevent aggregation and promote folding1, and few systems that can broadly enable protein folding by a different mechanism have been identified. Moreover, proteins that contain the extensively charged poly-Asp/Glu (polyD/E) region are common in eukaryotic proteomes2, but their biochemical activities remain undefined. Here we show that DAXX, a polyD/E protein that has been implicated in diverse cellular processes3-10, possesses several protein-folding activities. DAXX prevents aggregation, solubilizes pre-existing aggregates and unfolds misfolded species of model substrates and neurodegeneration-associated proteins. Notably, DAXX effectively prevents and reverses aggregation of its in vivo-validated client proteins, the tumour suppressor p53 and its principal antagonist MDM2. DAXX can also restore native conformation and function to tumour-associated, aggregation-prone p53 mutants, reducing their oncogenic properties. These DAXX activities are ATP-independent and instead rely on the polyD/E region. Other polyD/E proteins, including ANP32A and SET, can also function as stand-alone, ATP-independent molecular chaperones, disaggregases and unfoldases. Thus, polyD/E proteins probably constitute a multifunctional protein quality control system that operates via a distinctive mechanism.

DOI: https://doi.org/10.1038/s41586-021-03824-5
Front Cell Dev Biol. 2021 ;9 715200

Role of Autophagy in the Maintenance of Stemness in Adult Stem Cells: A Disease-Relevant Mechanism of Action.

Shanshan Chen, Wenqi Wang, Hor-Yue Tan, Yuanjun Lu, Zhiping Li, Yidi Qu, Ning Wang, Di Wang.

  Autophagy is an intracellular scavenging mechanism induced to eliminate damaged, denatured, or senescent macromolecular substances and organelles in the body. The regulation of autophagy plays essential roles in the processes of cellular homeostasis and senescence. Dysregulated autophagy is a common feature of several human diseases, including cancers and neurodegenerative disorders. The initiation and development of these disorders have been shown to be associated with the maintenance of disease-specific stem cell compartments. In this review, we summarize recent advances in our understanding of the role of autophagy in the maintenance of stemness. Specifically, we focus on the intersection between autophagy and adult stem cells in the initiation and progression of specific diseases. Accordingly, this review highlights the role of autophagy in stemness maintenance from the perspective of disease-associated mechanisms, which may be fundamental to our understanding of the pathogeneses of human diseases and the development of effective therapies.

Keywords:  adult stem cells; autophagy; cancers; differentiation; proliferation; self-renewal

DOI:  https://doi.org/10.3389/fcell.2021.715200
Adv Sci (Weinh). 2021 Aug 16. e2101912

Erythrocytes, a New Contributor to Age-Associated Loss of Blood-Brain Barrier Integrity.

Payam Amiri, Jonalyn DeCastro, Joshua Littig, Hsiang-Wei Lu, Chao Liu, Irina Conboy, Kiana Aran.

  Blood exchanges between young and old partners demonstrate old blood has a detrimental effect on brain health of young animals. Previous studies primarily investigate soluble blood factors, such as transforming growth factor-beta, on the brain and the blood-brain barrier (BBB). However, the role of blood cellular components, particularly erythrocytes, has not been defined. Erythrocyte morphology and rigidity change as mammals age, altering their transport within the capillary bed. This impacts downstream biological events, such as the release of reactive oxygen species and hemoglobin, potentially compromising the BBB. Here, a micro electrical BBB (µE-BBB), with cocultured endothelial and astrocytic cells, and a built-in trans-endothelial electrical resistance (TEER) system is described to monitor the effect of capillary shear stress on erythrocytes derived from young and old mice and people and the subsequent effects of these cells on BBB integrity. This is monitored by the passage of fluorescein isothiocyanate-dextran and real-time profiling of TEER across the BBB after old and young erythrocyte exposure. Compared to young erythrocytes, old erythrocytes induce an increased permeability by 42% and diminished TEER by 2.9% of the µE-BBB. These results suggest that changes in circulating erythrocytes are a biomarker of aging in the context of BBB integrity.

Keywords:  aging; blood-brain barriers; erythrocytes; microfluidics; organ-on-a-chips

DOI:  https://doi.org/10.1002/advs.202101912
Cell Rep. 2021 Aug 17. pii: S2211-1247(21)00994-3. [Epub ahead of print]36(7): 109560

Empirical versus theoretical power and type I error (false-positive) rates estimated from real murine aging research data.

Irene Alfaras, Keisuke Ejima, Camila Vieira Ligo Teixeira, Clara Di Germanio, Sarah J Mitchell, Samuel Hamilton, Luigi Ferrucci, Nathan L Price, David B Allison, Michel Bernier, Rafael de Cabo.

  We assess the degree of phenotypic variation in a cohort of 24-month-old male C57BL/6 mice. Because murine studies often use small sample sizes, if the commonly relied upon assumption of a normal distribution of residuals is not met, it may inflate type I error rates. In this study, 3-20 mice are resampled from the empirical distributions of 376 mice to create plasmodes, an approach for computing type I error rates and power for commonly used statistical tests without assuming a normal distribution of residuals. While all of the phenotypic and metabolic variables studied show considerable variability, the number of animals required to achieve adequate power is markedly different depending on the statistical test being performed. Overall, this work provides an analysis with which researchers can make informed decisions about the sample size required to achieve statistical power from specific measurements without a priori assumptions of a theoretical distribution.

Keywords:  Kaplan-Meier; aging phenotypes; gate speed; mouse aging; mouse phenotypes; plasmode; power calculation; respiratory exchange ratio; survival; type I error

DOI:  https://doi.org/10.1016/j.celrep.2021.109560
Nature. 2021 Aug 16.

Ubiquitin protein helps cells to recover from stress.

Titus Franzmann, Simon Alberti.



Keywords:  Cell biology; Molecular biology

DOI:  https://doi.org/10.1038/d41586-021-02197-z
Circ Res. 2021 Aug 18.

Filamin C Cardiomyopathy Variants Cause Protein and Lysosome Accumulation.

Radhika Agarwal, Joao Paulo, Christopher N Toepfer, Jourdan K Ewoldt, Subramanian Sundaram, Anant Chopra, Qi Zhang, Joshua Gorham, Steven DePalma, Christopher S Chen, Steven Gygi, Christine E Seidman, Jonathan G Seidman.

Rationale: Dominant heterozygous variants in Filamin C (FLNC) cause diverse cardiomyopathies, though the underlying molecular mechanisms remain poorly understood. Objective: We aimed to define the molecular mechanisms by which FLNC variants altered human cardiomyocyte gene and protein expression, sarcomere structure, and contractile performance. Methods and Results: Using CRISPR/Cas9, we introduced FLNC variants into human cardiomyocytes derived from induced pluripotent stem cells (hiPSC-CMs). We compared isogenic hiPSC-CMs with normal (WT), ablated expression (FLNC-/-) or haploinsufficiency (FLNC+/-) that causes DCM. We also studied a heterozygous in-frame deletion (FLNC+/∆7aa) which did not affect FLNC expression but caused aggregate formation, similar to FLNC variants associated with hypertrophic cardiomyopathy (HCM). FLNC-/- hiPSC-CMs demonstrated profound sarcomere misassembly and reduced contractility. While sarcomere formation and function were unaffected in FLNC+/- and FLNC+/∆7aa hiPSC-CMs, these heterozygous variants caused increases in lysosome content, enhancement of autophagic flux, and accumulation of FLNC-binding partners and Z-disc proteins. Conclusions: FLNC expression is required for sarcomere organization and physiologic function. Variants that produce misfolded FLNC proteins cause the accumulation of FLNC and FLNC binding partners which leads to increased lysosome expression and activation of autophagic pathways. Surprisingly, similar pathways were activated in FLNC haploinsufficient hiPSC-CMs, likely initiated by the loss of stoichiometric FLNC protein interactions and impaired turnover of proteins at the Z-disc. These results indicate that both FLNC haploinsufficient variants and variants that produce misfolded FLNC protein cause disease by similar proteotoxic mechanisms, and indicate the therapeutic potential for augmenting protein degradative pathways to treat a wide range of FLNC-related cardiomyopathies.

DOI: https://doi.org/10.1161/CIRCRESAHA.120.317076
In Vivo. 2021 Sep-Oct;35(5):35(5): 2609-2620

Autophagy Promoted Neural Differentiation of Human Placenta-derived Mesenchymal Stem Cells.

Areechun Sotthibundhu, Pattamon Muangchan, Ruchee Phonchai, Wilasinee Promjantuek, Nipha Chaicharoenaudomrung, Phongsakorn Kunhorm, Parinya Noisa.

  BACKGROUND/AIM: Human placenta-derived mesenchymal stem cells (hPMSCs) are multipotent and possess neurogenicity. Numerous studies have shown that Notch inhibition and DNA demethylation promote neural differentiation. Here, we investigated the modulation of autophagy during neural differentiation of hPMSCs, induced by DAPT and 5-Azacytidine.MATERIALS AND METHODS: hPMSCs were treated with DAPT to induce neural differentiation, and the autophagy regulating molecules were used to assess the impact of autophagy on neural differentiation.
RESULTS: The hPMSCs presented with typical mesenchymal stem cell phenotypes, in which the majority of cells expressed CD73, CD90 and CD105. hPMSCs were multipotent, capable of differentiating into mesodermal cells. After treatment with DAPT, hPMSCs upregulated the expression of neuronal genes including SOX2, Nestin, and βIII-tubulin, and the autophagy genes LC3I/II and Beclin. These genes were further increased when 5-Azacytidine was co-supplemented in the culture medium. The inhibition of autophagy by chloroquine impeded the neural differentiation of hPMSCs, marked by the downregulation of βIII-tubulin, while the activation of autophagy by valproic acid (VPA) instigated the emergence of βIII-tubulin-positive cells.
CONCLUSION: During the differentiation process, autophagy was modulated, implying that autophagy could play a significant role during the differentiation of these cells. The blockage and stimulation of autophagy could either hinder or induce the formation of neural-like cells, respectively. Therefore, the refinement of autophagic activity at an appropriate level might improve the efficiency of stem cell differentiation.

Keywords:  Human placenta; autophagy; mesenchymal stem cells; neural differentiation; notch signaling

DOI:  https://doi.org/10.21873/invivo.12543
Metab Brain Dis. 2021 Aug 18.

Neurovascular dysfunction and vascular amyloid accumulation as early events in Alzheimer's disease.

Ricardo Apátiga-Pérez, Luis O Soto-Rojas, B Berenice Campa-Córdoba, Nabil Itzi Luna-Viramontes, Elvis Cuevas, Ignacio Villanueva-Fierro, Miguel Angel Ontiveros-Torres, Marely Bravo-Muñoz, Paola Flores-Rodríguez, Linda Garcés-Ramirez, Fidel de la Cruz, José Francisco Montiel-Sosa, Mar Pacheco-Herrero, José Luna-Muñoz.

  Alzheimer's disease (AD) is clinically characterized by a progressive loss of cognitive functions and short-term memory. AD patients present two distinctive neuropathological lesions: neuritic plaques and neurofibrillary tangles (NFTs), constituted of beta-amyloid peptide (Aβ) and phosphorylated and truncated tau proteins. Aβ deposits around cerebral blood vessels (cerebral amyloid angiopathy, CAA) is a major contributor to vascular dysfunction in AD. Vascular amyloid deposits could be early events in AD due to dysfunction in the neurovascular unit (NVU) and the blood-brain barrier (BBB), deterioration of the gliovascular unit, and/or decrease of cerebral blood flow (CBF). These pathological events can lead to decreased Aβ clearance, facilitate a neuroinflammatory environment as well as synaptic dysfunction and, finally, lead to neurodegeneration. Here, we review the histopathological AD hallmarks and discuss the two-hit vascular hypothesis of AD, emphasizing the role of neurovascular dysfunction as an early factor that favors vascular Aβ aggregation and neurodegeneration. Addtionally, we emphasize that pericyte degeneration is a key and early element in AD that can trigger amyloid vascular accumulation and NVU/BBB dysfunction. Further research is required to better understand the early pathophysiological mechanisms associated with NVU alteration and CAA to generate early biomarkers and timely treatments for AD.

Keywords:  Alzheimer´s disease; Cerebral amyloid angiopathy; Neuroinflammation; Neurovascular dysfunction; Pericyte degeneration

DOI:  https://doi.org/10.1007/s11011-021-00814-4
Front Cell Dev Biol. 2021 ;9 697578

Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer's Disease.

Woo-In Ryu, Bruce M Cohen, Kai-C Sonntag.

  Sporadic or late-onset Alzheimer's disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.

Keywords:  Alzheimer’s disease; bioenergetics; cellular platform; disease modeling; metabolism; personalized medicine; pluripotent stem cell (PSC)

DOI:  https://doi.org/10.3389/fcell.2021.697578
Ageing Res Rev. 2021 Aug 14. pii: S1568-1637(21)00194-X. [Epub ahead of print] 101447

Targeting impaired adult hippocampal neurogenesis in ageing by leveraging intrinsic mechanisms regulating Neural Stem Cell activity.

Sébastien Gillotin, Vishal Sahni, Tjaša Lepko, Maya A Hanspal, Jina E Swartz, Zoi Alexopoulou, Fiona H Marshall.

  Deficits in adult neurogenesis may contribute to the aetiology of many neurodevelopmental, psychiatric and neurodegenerative diseases. Genetic ablation of neurogenesis provides proof of concept that adult neurogenesis is required to sustain complex and dynamic cognitive functions, such as learning and memory, mostly by providing a high degree of plasticity to neuronal circuits. In addition, adult neurogenesis is reactive to external stimuli and the environment making it particularly susceptible to impairment and consequently contributing to comorbidity. In the human brain, the dentate gyrus of the hippocampus is the main active source of neural stem cells that generate granule neurons throughout life. The regulation and preservation of the pool of neural stem cells is central to ensure continuous and healthy adult hippocampal neurogenesis (AHN). Recent advances in genetic and metabolic profiling alongside development of more predictive animal models have contributed to the development of new concepts and the emergence of molecular mechanisms that could pave the way to the implementation of new therapeutic strategies to treat neurological diseases. In this review, we discuss emerging molecular mechanisms underlying AHN that could be embraced in drug discovery to generate novel concepts and targets to treat diseases of ageing including neurodegeneration. To support this, we review cellular and molecular mechanisms that have recently been identified to assess how AHN is sustained throughout life and how AHN is associated with diseases. We also provide an outlook on strategies for developing correlated biomarkers that may accelerate the translation of pre-clinical and clinical data and review clinical trials for which modulation of AHN is part of the therapeutic strategy.

Keywords:  Adult Neurogenesis; Diseases of ageing; Hippocampus; Metabolism; Neural Stem Cells; Proteostasis

DOI:  https://doi.org/10.1016/j.arr.2021.101447
Endocrinology. 2021 Aug 18. pii: bqab173. [Epub ahead of print]

The pancreatic β cell response to secretory demands and adaption to stress.

Michael A Kalwat, Donalyn Scheuner, Karina Rodrigues Dos Santos, Decio L Eizirik, Melanie H Cobb.

  Pancreatic β cells dedicate much of their protein translation capacity to produce insulin to maintain glucose homeostasis. In response to increased secretory demand, β cells can compensate by increasing insulin production capability even in the face of protracted peripheral insulin resistance. The ability to amplify insulin secretion in response to hyperglycemia is a critical facet of β cell function, and the exact mechanisms by which this occurs have been studied for decades. To adapt to the constant and fast changing demands for insulin production, β cells utilize the unfolded protein response of the endoplasmic reticulum. Failure of these compensatory mechanisms contributes to both type 1 and 2 diabetes. Additionally, studies in which β cells are 'rested' by reducing endogenous insulin demand have shown promise as a therapeutic strategy that could be applied more broadly. Here we review recent findings in β cells pertaining to the metabolic amplifying pathway, the unfolded protein response, and potential advances in therapeutics based on β cell rest.

Keywords:  beta cell rest; endoplasmic reticulum stress; insulin secretion; pancreatic islet beta cell; unfolded protein response

DOI:  https://doi.org/10.1210/endocr/bqab173
Sci Adv. 2021 Aug;pii: eabh2307. [Epub ahead of print]7(34):

Planar cell polarity signaling components are a direct target of β-amyloid-associated degeneration of glutamatergic synapses.

Bo Feng, Andiara E Freitas, Lilach Gorodetski, Jingyi Wang, Runyi Tian, Yeo Rang Lee, Akumbir S Grewal, Yimin Zou.

The signaling pathway directly controlling the maintenance of adult glutamatergic synapses has not been well understood. Planar cell polarity (PCP) signaling components were recently shown to play essential roles in the formation of glutamatergic synapses. Here, we show that they are localized in the adult synapses and are essential for their maintenance. Synapse loss at early stages of Alzheimer's disease is thought to be induced by β-amyloid (Aβ) pathology. We found that oligomeric Aβ binds to Celsr3 and assists Vangl2 in disassembling synapses. Moreover, a Wnt receptor and regulator of PCP signaling, Ryk, is also required for Aβ-induced synapse loss. In the 5XFAD mouse model of Alzheimer's disease, Ryk conditional knockout or a function-blocking monoclonal Ryk antibody protected synapses and preserved cognitive function. We propose that tipping of the fine balance of Wnt/PCP signaling components in glutamatergic synapses may cause synapse degeneration in neurodegenerative disorders with Aβ pathology.

DOI: https://doi.org/10.1126/sciadv.abh2307
Exp Cell Res. 2021 Aug 16. pii: S0014-4827(21)00338-4. [Epub ahead of print] 112785

Disease modeling for Mucopolysaccharidosis type IIIB using patient derived induced pluripotent stem cells.

Wei Huang, Yu-Shan Cheng, Shu Yang, Manju Swaroop, Miao Xu, Wenwei Huang, Wei Zheng.

  Mucopolysaccharidosis type IIIB (MPS IIIB) is a lysosomal disease caused by mutations in the NAGLU gene encoding α-N-acetylglucosaminidase (NAGLU) which degrades heparan sulfate in lysosomes. Deficiency in NAGLU results in lysosomal accumulation of glycosaminoglycans (GAGs) and neurological symptoms. Currently, there is no effective treatment or cure for this disease. In this study, induced pluripotent stem cell lines were established from two MPS IIIB patient fibroblast lines and differentiated into neural stem cells and neurons. MPS IIIB neural stem cells exhibited NAGLU deficiency accompanied with GAG accumulation, as well as lysosomal enlargement and secondary lipid accumulation. Treatments with recombinant NAGLU, δ-tocopherol, and 2-hydroxypropyl-b-cyclodextrin significantly reduced the disease phenotypes in these cells. These results indicate the MPS IIIB neural stem cells and neurons have the disease relevant phenotype and can be used as a cell-based disease model system for evaluation of drug efficacy and compound screening for drug development.

Keywords:  2-hydroxypropyl-b-cyclodextrin; Mucopolysaccharidosis type IIIB; Sanfilippo syndrome B; iPSC disease model; lysosomal storage disease; δ-tocopherol

DOI:  https://doi.org/10.1016/j.yexcr.2021.112785
JMA J. 2021 Jul 15. 4(3): 207-215

Autophagy and Ciliogenesis.

Yasuhiro Yamamoto, Noboru Mizushima.

  Autophagy is a major intracellular degradation system and plays important roles in various physiological processes such as metabolic adaptation and intracellular homeostasis. It degrades intracellular components both randomly and selectively. Autophagic activity is tightly regulated primarily by nutrient availability, but also by other extracellular and intracellular signals. Growing evidence suggests that there are multiple links between autophagy and the primary cilium. The primary cilium is an organelle present on the cell surface and is important for keeping cellular integrity by transducing extracellular stimuli inside the cell. Recent studies have revealed that autophagy selectively degrades the ciliogenesis inhibitory proteins OFD1 and MYH9, promoting ciliogenesis. Conversely, autophagy also inhibits ciliogenesis under growth conditions. The primary cilium can also regulate autophagic activity. These findings suggest that the relationship between autophagy and the primary cilia is bidirectional, and that both are important for maintaining the normal function of various organs.

Keywords:  autophagy; ciliogenesis; ciliopathy

DOI:  https://doi.org/10.31662/jmaj.2021-0090
J Chem Phys. 2021 Aug 14. 155(6): 064102

Feedback control of protein aggregation.

Alexander J Dear, Thomas C T Michaels, Tuomas P J Knowles, L Mahadevan.

The self-assembly of peptides and proteins into amyloid fibrils plays a causative role in a wide range of increasingly common and currently incurable diseases. The molecular mechanisms underlying this process have recently been discovered, prompting the development of drugs that inhibit specific reaction steps as possible treatments for some of these disorders. A crucial part of treatment design is to determine how much drug to give and when to give it, informed by its efficacy and intrinsic toxicity. Since amyloid formation does not proceed at the same pace in different individuals, it is also important that treatment design is informed by local measurements of the extent of protein aggregation. Here, we use stochastic optimal control theory to determine treatment regimens for inhibitory drugs targeting several key reaction steps in protein aggregation, explicitly taking into account variability in the reaction kinetics. We demonstrate how these regimens may be updated "on the fly" as new measurements of the protein aggregate concentration become available, in principle, enabling treatments to be tailored to the individual. We find that treatment timing, duration, and drug dosage all depend strongly on the particular reaction step being targeted. Moreover, for some kinds of inhibitory drugs, the optimal regimen exhibits high sensitivity to stochastic fluctuations. Feedback controls tailored to the individual may therefore substantially increase the effectiveness of future treatments.

DOI: https://doi.org/10.1063/5.0055925
Am J Primatol. 2021 Aug 17. e23309

Nonhuman primates at the intersection of aging biology, chronic disease, and health: An introduction to the American journal of primatology special issue on aging, cognitive decline, and neuropathology in nonhuman primates.

Carol A Shively, Agnès Lacreuse, Brett M Frye, Emily S Rothwell, Manuel Moro.

  Aging across the Primate Order is poorly understood because ages of individuals are often unknown, there is a dearth of aged animals available for study, and because aging is best characterized by longitudinal studies which are difficult in long-lived species. The human population is aging rapidly, and advanced age is a primary risk factor for several chronic diseases and conditions that impact healthspan. As lifespan has increased, diseases and disorders of the central nervous system (CNS) have become more prevalent, and Alzheimer's disease and related dementias have become epidemic. Nonhuman primate (NHP) models are key to understanding the aging primate CNS. This Special Issue presents a review of current knowledge about NHP CNS aging across the Primate Order. Similarities and differences to human aging, and their implications for the validity of NHP models of aging are considered. Topics include aging-related brain structure and function, neuropathologies, cognitive performance, social behavior and social network characteristics, and physical, sensory, and motor function. Challenges to primate CNS aging research are discussed. Together, this collection of articles demonstrates the value of studying aging in a breadth of NHP models to advance our understanding of human and nonhuman primate aging and healthspan.

Keywords:  aging; alzheimer's disease; cognitive decline; gait speed; nonhuman primate

DOI:  https://doi.org/10.1002/ajp.23309
NPJ Aging Mech Dis. 2021 Aug 17. 7(1): 22

The killifish visual system as an in vivo model to study brain aging and rejuvenation.

Sophie Vanhunsel, Steven Bergmans, An Beckers, Isabelle Etienne, Jolien Van Houcke, Eve Seuntjens, Lut Arckens, Lies De Groef, Lieve Moons.

Worldwide, people are getting older, and this prolonged lifespan unfortunately also results in an increased prevalence of age-related neurodegenerative diseases, contributing to a diminished life quality of elderly. Age-associated neuropathies typically include diseases leading to dementia (Alzheimer's and Parkinson's disease), as well as eye diseases such as glaucoma and age-related macular degeneration. Despite many research attempts aiming to unravel aging processes and their involvement in neurodegeneration and functional decline, achieving healthy brain aging remains a challenge. The African turquoise killifish (Nothobranchius furzeri) is the shortest-lived reported vertebrate that can be bred in captivity and displays many of the aging hallmarks that have been described for human aging, which makes it a very promising biogerontology model. As vision decline is an important hallmark of aging as well as a manifestation of many neurodegenerative diseases, we performed a comprehensive characterization of this fish's aging visual system. Our work reveals several aging hallmarks in the killifish retina and brain that eventually result in a diminished visual performance. Moreover, we found evidence for the occurrence of neurodegenerative events in the old killifish retina. Altogether, we introduce the visual system of the fast-aging killifish as a valuable model to understand the cellular and molecular mechanisms underlying aging in the vertebrate central nervous system. These findings put forward the killifish for target validation as well as drug discovery for rejuvenating or neuroprotective therapies ensuring healthy aging.

DOI: https://doi.org/10.1038/s41514-021-00077-4
ChemMedChem. 2021 Aug 16.

Formaldehyde-crosslinked nontoxic A β monomer to form the toxic A β dimers and aggregates: Pathogenicity and therapeutic perspectives.

Hang Zhao, Xuerong Huang, Zhiqian Tong.

  Alzheimer's disease (AD) is characterized by the presence of senile plaques in the brain. However, medicines targeting amyloid-beta (Aβ) have not achieved the expected clinical effects. This review focuses on the formation mechanism of the Aβ dimer (the basic unit of oligomers and fibrils) and its tremendous potential as a drug target . Recently, age-associated formaldehyde and Aβ-derived formaldehyde have been found to crosslink the nontoxic Aβ monomer to form the toxic dimers, oligomers and fibrils. Particularly, Aβ-induced formaldehyde accumulation and formaldehyde-promoted Aβ aggregation form a vicious cycle. Subsequently, formaldehyde initiates Aβ toxicity in both the early- and late-onset AD. These facts also explain why AD drugs targeting only Aβ do not have the desired therapeutic effects. Development of the nanoparticle-based medicines targeting both formaldehyde and Aβ dimer is a promising strategy for improving the drug efficacy by penetrating blood-brain barrier and extracellular space into the cortical neurons in AD patients.

Keywords:  Aβ dimer; Aβ monomer; blood-brain barrier (BBB); extracellular space (ECS); formaldehyde (FA)

DOI:  https://doi.org/10.1002/cmdc.202100428
STAR Protoc. 2021 Sep 17. 2(3): 100713

Protocol to study starvation-induced autophagy in developing rat neurons.

José Wojnacki, Sébastien Nola, Thierry Galli.

  Autophagy is being involved in an increasing number of cellular pathways. It now appears that autophagy stimulation and inhibition have complex effects in neurons. Here, we present a simple yet powerful protocol to induce autophagy in primary neurons in culture by partial nutrient deprivation, in neurons with or without transfection of plasmids encoding the Longin domain of VAMP7 or a nanobody directed against VAMP7. Although limited to cells in culture, this protocol can facilitate the study of autophagy in neurons. For complete details on the use and execution of this protocol, please refer to Wojnacki et al. (2020).

Keywords:  Antibody; Cell Biology; Cell culture; Microscopy; Neuroscience

DOI:  https://doi.org/10.1016/j.xpro.2021.100713
Brain Commun. 2021 ;3(3): fcab147

Soluble amyloid beta-containing aggregates are present throughout the brain at early stages of Alzheimer's disease.

Dimitrios I Sideris, John S H Danial, Derya Emin, Francesco S Ruggeri, Zengjie Xia, Yu P Zhang, Evgeniia Lobanova, Helen Dakin, Suman De, Alyssa Miller, Jason C Sang, Tuomas P J Knowles, Michele Vendruscolo, Graham Fraser, Damian Crowther, David Klenerman.

  Protein aggregation likely plays a key role in the initiation and spreading of Alzheimer's disease pathology through the brain. Soluble aggregates of amyloid beta are believed to play a key role in this process. However, the aggregates present in humans are still poorly characterized due to a lack of suitable methods required for characterizing the low concentration of heterogeneous aggregates present. We have used a variety of biophysical methods to characterize the aggregates present in human Alzheimer's disease brains at Braak stage III. We find soluble amyloid beta-containing aggregates in all regions of the brain up to 200 nm in length, capable of causing an inflammatory response. Rather than aggregates spreading through the brain as disease progresses, it appears that aggregation occurs all over the brain and that different brain regions are at earlier or later stages of the same process, with the later stages causing increased inflammation.

Keywords:  Alzheimer’s disease; amyloid beta 42; neurodegeneration; neuroinflammation; soluble aggregates

DOI:  https://doi.org/10.1093/braincomms/fcab147
Cell Calcium. 2021 Aug 05. pii: S0143-4160(21)00107-X. [Epub ahead of print]98 102453

Ca2+ handling at the mitochondria-ER contact sites in neurodegeneration.

Dmitry Lim, Giulia Dematteis, Laura Tapella, Armando A Genazzani, Tito Calì, Marisa Brini, Alexei Verkhratsky.

  Mitochondria-endoplasmic reticulum (ER) contact sites (MERCS) are morpho-functional units, formed at the loci of close apposition of the ER-forming endomembrane and outer mitochondrial membrane (OMM). These sites contribute to fundamental cellular processes including lipid biosynthesis, autophagy, apoptosis, ER-stress and calcium (Ca2+) signalling. At MERCS, Ca2+ ions are transferred from the ER directly to mitochondria through a core protein complex composed of inositol-1,4,5 trisphosphate receptor (InsP3R), voltage-gated anion channel 1 (VDAC1), mitochondrial calcium uniporter (MCU) and adaptor protein glucose-regulated protein 75 (Grp75); this complex is regulated by several associated proteins. Deregulation of ER-mitochondria Ca2+ transfer contributes to pathogenesis of neurodegenerative and other diseases. The efficacy of Ca2+ transfer between ER and mitochondria depends on the protein composition of MERCS, which controls ER-mitochondria interaction regulating, for example, the transversal distance between ER membrane and OMM and the extension of the longitudinal interface between ER and mitochondria. These parameters are altered in neurodegeneration. Here we overview the ER and mitochondrial Ca2+ homeostasis, the composition of ER-mitochondrial Ca2+ transfer machinery and alterations of the ER-mitochondria Ca2+ transfer in three major neurodegenerative diseases: motor neurone diseases, Parkinson disease and Alzheimer's disease.

Keywords:  Alzheimer's disease; Amyotrophic lateral sclerosis; Endoplasmic reticulum; Mitochondria; Mitochondria-ER contact sites; Motor neurone disease; Parkinson's disease

DOI:  https://doi.org/10.1016/j.ceca.2021.102453
J Alzheimers Dis. 2021 Aug 11.

A Specialized Nutritional Formulation Prevents Hippocampal Glial Activation and Memory Impairment Induced by Amyloid-β Oligomers in Mice.

Luciana Domett Siqueira, Ana Paula M Celes, Hellin Dos Santos, Sergio T Ferreira.

  BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia in the elderly and is characterized by progressive cognitive decline. Considerable evidence supports an important role of amyloid-β oligomers (AβOs) in the pathogenesis of AD, including the induction of aberrant glial activation and memory impairment.OBJECTIVE: We have investigated the protective actions of a nutritional formulation, denoted AZ formulation, on glial activation and memory deficits induced by intracerebroventricular (i.c.v.) infusion of AβOs in mice.
METHODS: Two-month-old male mice were treated orally with AZ formulation or isocaloric placebo for 30 consecutive days. Microglial and astrocytic activation were analyzed by immunohistochemistry in the hippocampus 10 days after i.c.v. infusion of AβOs (n = 5 mice per experimental condition). Memory loss was assessed by the novel object recognition (NOR) test (n = 6-10 mice per experimental condition).
RESULTS: Oral treatment with the AZ formulation prevented hippocampal microglial and astrocytic activation induced by i.c.v. infusion of AβOs. The AZ formulation further protected mice from AβO-induced memory impairment.
CONCLUSION: Results suggest that administration of the AZ formulation may comprise a promising preventative and non-pharmacological strategy to reduce brain inflammation and attenuate memory impairment in AD.

Keywords:  Alzheimer’s disease; amyloid-β ; astrocytes; memory; microglia; non-pharmacological approaches

DOI:  https://doi.org/10.3233/JAD-210139