bims-proned 2026-03-22 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2026–03–22
fourteen papers selected by
Verena Kohler, Umeå University

Ubiquitin signatures on aggregating proteins in neurodegeneration.
The α-synuclein proteostasis network and its translational applications in Parkinson's disease.
Small heat shock proteins HspB1 and HspB5 differentially alter the condensation and aggregation of the TDP-43 low-complexity domain.
Aggregation and membrane activity of mutant A30P alpha-synuclein on mitochondrial membranes.
The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's disease.
Direct current stimulation induced reduction in α-synuclein in primary neurons: targeting Parkinson's disease.
Verbascoside and echinacoside inhibits the fibrillation of human α-synuclein and disassembles mature fibrils.
The cross-linking activity of transglutaminase 2 drives α-Synuclein pathology in synucleinopathy models.
α-Synuclein oligomers slow down action potential firing and enhance dopamine release by increasing Cav2.2 currents in midbrain dopaminergic neurons.
Electrochemistry Reveals the Accelerating Effect of Fluorinated Compounds on Early-Stage Amyloid Fibril Aggregation.
Narrative Review: Intestinal α-Syn Oligomers as a Novel Pharmacological Target for Parkinson's Disease.
Inhibition of Aβ(40) peptide aggregation by Milk-derived Amyloid-like Protein Aggregates (MAPA).
Enzymes of physiological amyloidogenesis control pathological amyloid toxicity.
Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer's disease.

Essays Biochem. 2025 Dec 22. pii: EBC20253046. [Epub ahead of print]69(5):

Ubiquitin signatures on aggregating proteins in neurodegeneration.

Subhashree Sahoo, Amrita Arpita Padhy, Kummari Shivani, Ashish Misra, Parul Mishra.

  The aberrant accumulation of misfolded proteins marked by cellular dysfunction and progressive neuronal loss is the hallmark of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. This review examines the pivotal role of ubiquitin modifications in altering the fate of aggregation-prone proteins such as tau, α-synuclein, mutant huntingtin, TAR DNA-binding protein 43 and superoxide dismutase 1. The ubiquitin signatures identified by their linkage types, chain architectures and site specificities emerge as a complex regulatory language that influences the clearance, aggregation or cellular propagation of these aggregating proteins. The dysregulation of other components of the ubiquitin association pathways, such as impaired E3 ligases and deubiquitinases, also contributes to the inefficient protein disposal and disease progression. Understanding how ubiquitin signatures alter the spatiotemporal dynamics of aggregating proteins is critical for advancing our knowledge of disease biology. Here, we focus on the role of ubiquitin modifications and their associated regulators affecting protein fate and neurotoxicity, and highlight the current therapeutic strategies targeting the degradation of aggregating proteins to uncover potential avenues for treating neurodegenerative diseases.

Keywords:  autophagy; neurodegenerative disease; proteasome; ubiquitin; ubiquitin E3 ligases

DOI:  https://doi.org/10.1042/EBC20253046
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2513317123

The α-synuclein proteostasis network and its translational applications in Parkinson's disease.

Christine M Lim, Michele Vendruscolo.

  Parkinson's disease (PD) is a debilitating neurodegenerative condition that results in a loss of mobility and muscle control. A neuropathological hallmark of PD is the presence of aberrant inclusions, known as Lewy pathology, of which α-synuclein (α-Syn) is a major component. The accumulation of α-Syn may be due to an imbalance in the proteostasis system regulating α-Syn. To investigate this hypothesis, we delineated the proteostasis network (PN) of α-Syn in the human substantia nigra at the proteomic and transcriptomic level. We then defined an α-Syn proteostasis activity score (PAS) that quantifiably describes the relative activity of the α-Syn PN in promoting or inhibiting α-Syn aggregation. We report a corresponding PAS signature indicative of disease state, age-of-death in PD patients, and brain regional vulnerability to α-Syn aggregation in PD and healthy brains. After establishing the relevance of our network to PD, we developed a transcriptome-derived network model as an operational digital twin of the α-Syn PN in human substantia nigra cells from single-cell data and used it to prioritize candidate targets for PD. We then further showed the application of the α-Syn PN toward facilitating drug repurposing. Overall, this proof-of-concept study illustrates how our computational framework can identify and prioritize putative therapeutic targets and repurposing candidates for PD, providing testable hypotheses for experimental validation.

Keywords:  Parkinson’s disease; alpha-synuclein; protein homeostasis

DOI:  https://doi.org/10.1073/pnas.2513317123
Protein Sci. 2026 Apr;35(4): e70539

Small heat shock proteins HspB1 and HspB5 differentially alter the condensation and aggregation of the TDP-43 low-complexity domain.

Thomas B Walker, Joshua W Trowbridge, Shannon McMahon, Nicholas R Marzano, Lauren Rice, Justin J Yerbury, Heath Ecroyd, Luke McAlary.

  TAR DNA-binding protein 43 (TDP-43) is a nucleic acid-binding protein that regulates processes of mRNA metabolism, during which it undergoes condensation mediated by its C-terminal low-complexity domain (TDP-43LCD). TDP-43 aggregation and condensation are associated with neurodegenerative disease. However, the proteostasis mechanisms that regulate these processes remain elusive. Some evidence has shown that the molecular chaperone small heat shock protein HspB1 binds to and regulates the cytoplasmic phase separation of TDP-43, indicating that other small heat shock proteins may have similar effects. Here, we demonstrate divergent behaviors for HspB1 and its homolog HspB5 on TDP-43LCD condensation and aggregation. In addition to inhibiting TDP-43LCD aggregation, HspB1 partitions into TDP-43LCD condensates and increases the dynamic exchange of TDP-43LCD within condensates and with the surrounding solution. Phosphorylation-mimicking mutations within HspB1 enhance these effects. HspB5 inhibits TDP-43LCD aggregation more effectively than HspB1 and partitions into TDP-43LCD condensates, where it delays the pathological transition of the condensate to a gel/solid. We identify the N- and C-terminal regions of HspB1 and HspB5 to be crucial for the chaperone effects, and highlight the role of sequence diversity within these regions in defining small heat shock protein function. These findings demonstrate that HspB1 and HspB5 are regulators of TDP-43 phase separation and aggregation and may be potential therapeutic targets in mitigating toxic TDP-43 aggregation in neurodegenerative disease.

Keywords:  amyotrophic lateral sclerosis; chaperones; fibrillation; liquid–liquid phase separation; proteostasis

DOI:  https://doi.org/10.1002/pro.70539
Int J Biol Macromol. 2026 Mar 17. pii: S0141-8130(26)01417-0. [Epub ahead of print] 151491

Aggregation and membrane activity of mutant A30P alpha-synuclein on mitochondrial membranes.

Maja Herrera, Adam El Saghir, Silvia Mansueto, Stephanie Ghio, Giuliana Fusco, Alfonso De Simone, Neville Vassallo.

  The A30P point mutation in the α-synuclein (α-syn) protein is linked to a familial form of Parkinson's disease (PD), the most common motor neurodegenerative disorder. The association of α-syn with lipids in cellular membranes plays a key role in modulating the aggregation behavior of the protein, as well as its toxicity. Here, we studied the impact of the A30P mutation on the interaction of α-syn with mitochondrial membranes, since the interplay between α-syn aggregation and mitochondrial dysfunction is central for the pathogenic process in PD, but still not completely understood. Experiments using model vesicles with membranes enriched in the mitochondrial signature phospholipid cardiolipin (CL) demonstrated that these membranes markedly accelerate and promote the aggregation of A30P α-syn, with respect to the wild-type protein. In turn, A30P caused enhanced changes in membrane fluidity and permeabilization of CL-containing membranes. Moreover, utilizing single-channel planar bilayer measurements, A30P α-syn was shown to increase the membrane conductance in mito-mimetic bilayers, possibly by membrane thinning and incorporation of ion-conducting pores. The incubation of A30P α-syn with isolated mitochondria caused mitochondrial swelling, efflux of cytochrome c and lowered the mitochondrial membrane potential, all key indicators of mitochondrial membrane damage. Collectively, our results demonstrate that the A30P mutation aggravates the deleterious liaison between α-syn and CL-rich membranes, providing a mechanistic basis for mitochondrial dysfunction associated with this α-syn variant.

Keywords:  Alpha-synuclein A30P; Cardiolipin; Mitochondria; Parkinson's disease; Protein aggregation; Protein-lipid interactions

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.151491
PNAS Nexus. 2026 Mar;5(3): pgag034

The microtubule nexus linking amyloid beta and tau: A simple and unifying theory for the underlying cause of Alzheimer's disease.

Thomas A Shoff, Maxence Derbez-Morin, Peishan Cai, Ryan R Julian.

  Alzheimer's disease (AD) is defined by cognitive decline in conjunction with accumulation of aggregated amyloid β (Aβ) and tau, yet existing models of AD fail to provide a simple connection between Aβ and tau. However, microtubules provide an intriguing nexus for pathological interactions between the two. Tau binds to microtubules and is critical to maintaining their proper function. We demonstrate that Aβ also binds to microtubules with affinity comparable to that of tau itself. We hypothesize that displacement of tau by Aβ leads to microtubule dysfunction and facilitates tau phosphorylation and aggregation. Importantly, in this model, aggregation of Aβ is not the primary cause of toxicity, which allows many of the apparent contradictions between Aβ pathology and cognition to be rationalized. This model highlights the importance of both tau and Aβ and enables additional therapeutic and intervention strategies to be considered.

Keywords:  aging; amyloid; dementia; microtubule; neurodegeneration

DOI:  https://doi.org/10.1093/pnasnexus/pgag034
Brain Commun. 2026 ;8(2): fcag065

Direct current stimulation induced reduction in α-synuclein in primary neurons: targeting Parkinson's disease.

Sophie Bechkos, Scott D Ryan, Alysia Ross, Hongyu Sun, Shawn Hayley.

  Targeted electrical approaches to the treatment for Parkinson's disease include deep brain stimulation, which is effective for core motor symptoms, such as essential tremor. Interestingly, treating comorbid depressive symptoms in Parkinson's disease, using electroconvulsive therapy, also appears to help motor disability. But it is unclear whether such electrical strategies have any impact on the underlying disease processes of Parkinson's disease. Since aggregation of misfolded alpha-synuclein fibrils is a pathological hallmark of Parkinson's disease, this may be an important therapeutic target. To this end, we presently assessed whether direct current stimulation (DCS) of cortical neurons that were seeded with wild-type or A53T alpha-synuclein mutant pre-formed fibrils (PFFs) would reduce their aggregation. We found that both wild-type and A53T alpha-synuclein PFFs readily induced alpha-synuclein aggregation in primary cortical neurons and this effect was more pronounced at embryonic Day 17 (E17), compared to less mature E14-derived neurons. We did find that DCS time dependently reduced alpha-synuclein accumulation (phosphorylated and aggregate forms) within neurons and increased neuronal viability. Increased extracellular alpha-synuclein levels suggest that the DCS induced an increase in neuronal activity causing the clearance of the intracellular alpha-synuclein. These data have implications for non-invasive neuromodulation strategies to lower alpha-synuclein burden and possibly correct aberrant neuronal firing in Parkinson's disease and other alpha-synucleinopathies.

Keywords:  Parkinson’s disease; cell culture; deep brain stimulation; neurodegeneration; α-synuclein

DOI:  https://doi.org/10.1093/braincomms/fcag065
Bioorg Chem. 2026 Mar 04. pii: S0045-2068(26)00213-0. [Epub ahead of print]174 109677

Verbascoside and echinacoside inhibits the fibrillation of human α-synuclein and disassembles mature fibrils.

Jieshi Zhong, Haiyang Luo, Chenyang Liu, Suying Duan, Honglin Zheng, Yaochong Zhang, Wenzhuo Zhao, Tuo Wang, Si Yan, Xianwen Wei, Yuming Xu.

  Targeting α-synuclein (α-syn) amyloid fibrils is considered a promising therapeutic strategy for Parkinson's disease (PD). In this study, we systematically evaluated the direct regulatory effects of two polyphenolic small molecules, Echinacoside (ECH) and Verbascoside (VER), on the amyloidogenesis of human α-syn. A combination of Thioflavin T (ThT) fluorescence kinetics, secondary-structure analyses (CD and FTIR spectroscopy), morphological characterization (TEM, AFM, and DLS), and molecular docking was employed to comprehensively assess their abilities to inhibit α-syn fibril formation and to disassemble preformed fibrils. Both ECH and VER inhibited α-syn fibrillation and promoted the disassembly of mature fibrils in a dose-dependent manner, and alleviated the cytotoxic effects of mature α-syn fibrils on SH-SY5Y cells. Molecular docking analysis revealed that VER preferentially associates with the hydrophobic NAC core of α-syn through multiple non-covalent interactions, thereby stabilizing its binding to amyloid fibrils. Collectively, these findings demonstrate that the phenylethanoid glycosides VER and ECH can directly interfere with α-syn amyloidogenesis, providing experimental support for the development of α-syn-targeted therapeutic strategies for Parkinson's disease.

Keywords:  Amyloidogenesis; Echinacoside; Polyphenols; Verbascoside; α-Synuclein

DOI:  https://doi.org/10.1016/j.bioorg.2026.109677
Proc Natl Acad Sci U S A. 2026 Mar 24. 123(12): e2517886123

The cross-linking activity of transglutaminase 2 drives α-Synuclein pathology in synucleinopathy models.

Kambiz Hassanzadeh, Jun Liu, Jie Zhang, Mohadeseh Abouhosseini Tabari, Santhosh Maddila, M Maral Mouradian.

  Transglutaminase 2 (TG2) is implicated in synucleinopathies including Parkinson's disease (PD) and dementia with Lewy bodies, as it promotes α-Synuclein (α-Syn) aggregation in vitro, and evidence for its activity is detected in Lewy bodies in human postmortem brains. Additionally, TG2 overexpression exacerbates α-Syn toxicity in double transgenic mice, while TG2 deletion mitigates the phenotype of α-Syn transgenic mice. Considering that TG2 is a multidomain and multifunctional protein, the present study was carried out to confirm that the transamidase activity of TG2 specifically drives its pathogenetic role in synucleinopathies. We generated transgenic mice expressing a catalytically inactive W241A mutant TG2 and compared them with TG2-overexpressing and TG2 knockout mice using the α-Syn preformed fibril (PFF) model. We also examined double transgenic mice coexpressing human α-Syn with either wild-type TG2 or mutant TG2, alongside α-Syn single transgenic controls. 6 mo post-PFF injection, or at 6 mo of age in the double transgenic lines, the exacerbation of the behavioral and neuropathological phenotype seen with TG2 overexpression was lost with mutant TG2 overexpression in both models. Parallel findings were replicated in PD patient induced pluripotent stem cell-derived dopaminergic neurons. These findings indicate that the cross-linking activity of TG2 plays a pivotal role in α-Syn aggregation and toxicity, underscoring its significance as a therapeutic target in synucleinopathies.

Keywords:  Parkinson’s disease; dementia with Lewy bodies; neurodegeneration; transglutaminase 2; α-Synuclein

DOI:  https://doi.org/10.1073/pnas.2517886123
J Physiol. 2026 Mar 16.

α-Synuclein oligomers slow down action potential firing and enhance dopamine release by increasing Cav2.2 currents in midbrain dopaminergic neurons.

Giulia Tomagra, Anthony Battaglia, Claudio Franchino, Sara Bonzano, Federico Picollo, Giuseppe Chiantia, Antonio de Iure, Paolo Calabresi, Barbara Picconi, Emilio Carbone, Silvia De Marchis, Andrea Marcantoni, Valentina Carabelli.

  The spontaneous firing activity of substantia nigra (SN) dopaminergic (DA) neurons is finely tuned by the autocrine inhibition mediated by D2 DA autoreceptors (D2-ARs) that activate GIRK2 channels. Despite this regulatory mechanism, the vulnerability of SN DA neurons may nevertheless increase due to an altered spontaneous firing activity of DA neurons, Ca2+ dishomeostasis, mitochondrial stress, high dendritic arborization, aggregation of α-synuclein (α-syn), α-syn mutations, reduced levels of calbindin protein, etc. Although the intraneuronal accumulation and the spreading of misfolded α-syn is a hallmark of full-blown Parkinson's disease, the effects produced by α-syn aggregation on neuronal functionality at the early onset of neurodegeneration are still of debate. We previously reported that α-syn oligomers in the extracellular medium drastically inhibit the firing rate of midbrain neurons and significantly impair burst generation and network synchronization. Here, by combining conventional electrophysiology and cutting-edge technology of micro-graphitized diamond micro-electrode arrays, we confirm that exogenous α-syn effectively slows down the firing rate of SN DA neurons, but it also selectively upregulates Cav2.2 (N-type) Ca2+ currents and consequently Ca2+-dependent DA release. Thus, our data uncover a novel regulatory mechanism in SN DA neurons and demonstrate that exogenous α-syn alters the interplay among Ca2+ entry, spontaneous firing and DA release causing DA accumulation in the extracellular milieu and intracellular Ca2+ overload. Both processes may represent a target for future investigations to better understand the initial phases of SN DA neuron degeneration. KEY POINTS: We combined conventional electrophysiology and micro-graphitized diamond multi-electrode arrays to investigate the effect of exogeneous α-synuclein on cultured midbrain dopaminergic neurons isolated from substantia nigra. α-Synuclein oligomers slow down the firing rate of dopaminergic neurons and up-regulate Cav2.2 (N-type) Ca2+ currents. Raised Cav2.2 currents in turn increase the depolarization-evoked dopamine release and the frequency of quantal exocytotic events. Overall, this mechanism causes dopamine accumulation in the extracellular milieu and intracellular Ca2+ overload.

Keywords:  Cav2.2. channels; alpha‐synuclein; diamond‐based micro‐electrode arrays; quantal dopamine release; spontaneous firing

DOI:  https://doi.org/10.1113/JP288914
Anal Chem. 2026 Mar 19.

Electrochemistry Reveals the Accelerating Effect of Fluorinated Compounds on Early-Stage Amyloid Fibril Aggregation.

Guoyuan Ren, Xinyue Wang, Yuqing Cai, Yongyue Yin, Tianyuan Wang, Yufeng Wang, Huan Wei, Meining Zhang.

Fluorinated compounds, which are widely used and environmentally persistent, represent important potential triggers of amyloid fibril aggregation associated with neurodegenerative diseases. However, their specific effects on early-stage oligomers and protofibrils remain poorly understood. Research progress is constrained by conventional analytical methods due to the inability to monitor dynamics in aqueous environments and insufficient sensitivity for detecting early aggregates with limited β-sheet content, existing in an irregular morphology formed during oligomer-to-protofibril transition. To address this analytical gap, we establish an electrochemiluminescence (ECL) approach for monitoring of irregular oligomers with limited β-sheet content, which is based on the collisions between [Ru(bpy)2dppz]2+-bound irregular oligomers and radical trin-propylamine (TPrA·) that are electrochemically generated from TPrA oxidation in the diffusion layer at a carbon fiber microelectrode. The results demonstrate that the produced ECL intensity is related to the aggregate extent of [Ru(bpy)2dppz]2+-bound irregular oligomer because of excessive TPrA· radicals at the diffusion layer of the microelectrode. By integrating our electrochemical collision previously developed and this ECL method, we investigate the impact of heptafluorobutyric acid (HFBA) on early-stage amyloid fibril aggregation. The results demonstrate that HFBA accelerates the aggregation of early-stage amyloid fibrils. Molecular docking simulations further reveal that the accelerated aggregation of early-stage amyloid fibrils may be attributed to the hydrophobic and electronegative properties of HFBA, which lower the energy barrier for protein aggregation. This work not only provides crucial insights into the environmental factors in neurodegenerative pathogenesis but also offers prospective guidance for biosafety assessment and rational application of related compounds.

DOI: https://doi.org/10.1021/acs.analchem.5c07745
Neurogastroenterol Motil. 2026 Mar;38(3): e70289

Narrative Review: Intestinal α-Syn Oligomers as a Novel Pharmacological Target for Parkinson's Disease.

Qian Shen, Anran Lv, Yaxin Li, Peizhi Liu, Jibao Yang, Shaoxia Wang, Hong Guo.

   BACKGROUND AND AIMS: Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic neurons and neurological dysfunctions. The aggregation of abnormal α-synuclein (α-Syn) is closely associated with neuronal damage and acts as the major pathogenic driver mediating neurotoxicity. As critical intermediates in the aggregation cascade, α-Syn oligomers are regarded as the most neurotoxic species, which are widely distributed in both the central and peripheral nervous systems and contribute to the initiation and progression of PD. The gut-brain axis has attracted increasing attention, with a focus on the generation and propagation of gut-derived α-Syn oligomers, which can be promoted by chronic gut inflammation, gut microbiota dysbiosis, genetic mutations, and environmental factors. In this paper, we systematically elaborate on the formation of α-Syn oligomers and their transmission into the central nervous system, discuss existing therapeutic strategies targeting α-Syn oligomers, and analyze emerging prospects for future interventions.
RESULTS: This review integrates and analyzes available evidence regarding the biogenesis, gut-to-brain propagation, and pathogenic roles of α-Syn oligomers in PD. It also summarizes the current progress of therapeutic approaches targeting α-Syn oligomers and evaluates their potential value.
CONCLUSION: This review not only provides novel insights into pathogenetic mechanisms of PD but also highlights the therapeutic feasibility of targeting gut-derived α-Syn oligomers as a potential strategy for PD treatment.

Keywords:  Parkinson's disease; neurotoxicity; the gut‐brain axis; α‐Syn oligomers

DOI:  https://doi.org/10.1111/nmo.70289
Biol Chem. 2026 Mar 19.

Inhibition of Aβ(40) peptide aggregation by Milk-derived Amyloid-like Protein Aggregates (MAPA).

Shweta Malik, Indranil De, Abhishek Singh Yadav, Vikash Poonia, Kritika Gaur, Pankaj Goyal, Manish Singh, Jay Kant Yadav.

  Recent studies have identified Aβ peptides in human gut epithelial cells, along with several amyloid-forming proteins and peptides in the gut lumen. These findings suggest that Aβ or other amyloid-like molecules originating from the gut may contribute to the involvement of the gastrointestinal system in the development of Alzheimer's disease (AD) pathology. Modulating the aggregation behaviour of Aβ and other amyloid forming peptides/proteins present in the gut may represent novel strategy to mitigate AD pathology. This study explores the use of Milk-derived Amyloid-like Protein Aggregates (MAPA) to inhibit Aβ(40) aggregation in vitro. MAPA's inhibitory effects were assessed using amyloid dye-binding assays (Thioflavin T, Congo Red, and ANS) and transmission electron microscopy. Toxicity assays showed that the MAPA significantly reduced Aβ(40)-induced neuronal death. Fluorescence quenching suggest MAPA physically interacts with Aβ(40) to prevent its aggregation. By blocking Aβ aggregation and reducing its neurotoxicity, MAPA presents a promising organic strategy to counteract AD progression influenced by gut factors. These findings open new avenues for AD prevention and the disease management, especially via dietary interventions targeting the gastro-intestinal system.

Keywords:  Alzheimer’s disease; Aβ peptide; Milk-derived Amyloids-like Protein Aggregates; gut-brain axis; neurotoxicity

DOI:  https://doi.org/10.1515/hsz-2025-0208
Life Sci Alliance. 2026 Jun;pii: e202503493. [Epub ahead of print]9(6):

Enzymes of physiological amyloidogenesis control pathological amyloid toxicity.

Michael Bokros, Alex Grunfeld, Nathan C Balukoff, Jessica Bouviere, Eléonore Beurel, Stephen Lee.

Physiological amyloidogenesis drives the formation of functional amyloids involved in various biochemical pathways. We recently showed that the RNA tailing and decay machinery controls the maturation of intracellular amyloid-like aggregates. This raises the question of whether enzymes that participate in the maturation of physiological amyloids are involved in pathological amyloidogenesis implicated in human proteopathies. Using Caenorhabditis elegans and mouse models of pathological amyloids, we show that manipulating the RNA tailing-decay axis alters the toxicity of β-amyloid and α-synuclein involved in Alzheimer's and Parkinson's diseases, respectively. The RNA tailing enzymes TENT4b and TENT2 protect against β-amyloid- and α-synuclein-induced toxicity by facilitating the formation of nontoxic amyloidogenic assemblies. In contrast, the RNA exonuclease Exosc10 potentiates pathological amyloid toxicity. Remarkably, Exosc10 depletion prevents cognitive decline and restores memory in two different mouse models of β-amyloid neurotoxicity. Taken together, these results suggest that pathways of physiological amyloidogenesis participate in pathological amyloid etiology.

DOI: https://doi.org/10.26508/lsa.202503493
Ageing Res Rev. 2026 Mar 18. pii: S1568-1637(26)00089-9. [Epub ahead of print]118 103097

Tau phosphorylation homeostasis: Mechanisms, targets, and therapeutic implications in Alzheimer's disease.

Shengwen Lu, Shi Qiu, Yu Guan, Aihua Zhang, Qiqi Zhao.

  Neurofibrillary tangles, composed of excessively phosphorylated tau, are a core neuropathological hallmark of Alzheimer's disease (AD). However, therapeutic strategies aimed at directly clearing neurofibrillary tangles have demonstrated limited clinical efficacy, shifting the research focus towards the fundamental underlying mechanism- the dysregulation of tau phosphorylation. Evidence indicates that tau physiological phosphorylation is indispensable for microtubule stability and normal neuronal function, while its aberrant hyperphosphorylation drives neurodegeneration. Consequently, restoring tau phosphorylation homeostasis, rather than merely eliminating the pathological protein, has emerged as a promising therapeutic paradigm. This review systematically delineates the physiological functions and pathological mechanisms of tau phosphorylation, highlighting its central role in AD pathogenesis. We summarize recent advances in drug development targeting key kinases and phosphatases, and discuss the diagnostic value and application prospects of tau phosphorylation biomarkers. Ultimately, this study aims to provide a theoretical framework for novel precision treatment strategies in AD.

Keywords:  Alzheimer's disease; Neurodegenerative diseases; Signaling pathways; Tau phosphorylation; Therapeutic targets

DOI:  https://doi.org/10.1016/j.arr.2026.103097