bims-amyloi 2026-10-11 papers

bims-amyloi

Biomed News

on Amyloid

Issue of 2026–10–11
six papers selected by
Alexander Röntgen, University of Cambridge

AA and Parkinson's Disease.
Amyloid-β plaque diversity across brain regions in Alzheimer's disease and its relation to major clinicopathological traits.
Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.
Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.
Therapeutic potential of proline-rich peptide-1 (PRP-1) in counteracting amyloid-β-mediated cortical and hippocampal neurodegeneration in a rat model.
The Amyloid State of Mutant p53 in Cancer.

Rev Physiol Biochem Pharmacol. 2027 ;188 187-202

AA and Parkinson's Disease.

Undurti N Das.

  Parkinson's disease (PD) is due to degeneration of dopaminergic neurons in substantia nigra pars compacta. PD neuropathology is characterized by the presence of Lewy bodies that contain aggregated α-synuclein, which has been implicated in a range of interactions with phospholipid membranes and free fatty acids. I propose that α-synuclein interacts with arachidonic acid (AA) to regulate the function of dopaminergic neurons. α-Synuclein sequesters AA, whereas AA induces the formation of oligomers that are alpha-helical; resistant to fibril formation; more prone to disaggregation, enzymatic digestion, and degradation; and hence less likely to cause neuronal damage and induce PD. In addition, AA interacts with syntaxin to regulate exocytosis of various neurotransmitters, including dopamine. AA has potent anti-inflammatory actions, serves as a mechanotransducer, influences cell membrane fluidity, enhances glucose uptake by neurons, possesses cytoprotective action, and is the precursor of anti-inflammatory lipoxin A4 (LXA4), actions that maintain the integrity of dopaminergic neurons in the substantia nigra pars compacta. The dynamic equilibrium among α-synuclein, syntaxin, AA, exocytosis of dopamine, formation of LXA4, and the inflammatory process is involved in the development of PD. This implies that deficiency of AA can render dopaminergic neurons susceptible to inflammatory neurodegeneration and development of PD. Hence, it is proposed that administration of AA and DHA (that are present in substantial amounts in the brain) can be used in the prevention and management of PD.

Keywords:  Exocytosis; Fibril; Lewy bodies; Parkinson’s disease; Syntaxin; α-Synuclein

DOI:  https://doi.org/10.1007/978-981-92-5964-9_8
Acta Neuropathol. 2026 Oct 07. pii: 46. [Epub ahead of print]152(1):

Amyloid-β plaque diversity across brain regions in Alzheimer's disease and its relation to major clinicopathological traits.

Antonia Neubauer, Paul Feyen, Susanna Pekrun, Sigrun Roeber, Viktoria Ruf, Felix L Strübing, Jochen Herms.

  Amyloid beta (Aβ) deposition and tau accumulation are neuropathological hallmarks of Alzheimer's disease (AD). While Aβ deposits present with a wide morphological variety, a comprehensive, cross-regional overview of Aβ plaque composition in AD and associations with clinicopathological traits are missing. In this study, we systematically documented the abundance and morphological diversity of Aβ plaques in up to 23 brain regions of 84 advanced AD cases. Deposits were segmented with a random forest pixel classifier in 4G8 diaminobenzidine stains and classified into six classes using a convolutional neural network (cored, diffuse light, diffuse dense, compact, small dense plaques, cerebral amyloid angiopathy (CAA)). Deposit counts were correlated between classes, regions, and tau load using Pearson correlation. Associations between plaque densities and co-pathologies, sex, ApoE, familial vs. sporadic cases, age at clinical onset, disease duration, and age at death were examined. Our classification model achieved a recall of 81.5% and a precision of 82.4% in the test set. Cortical brain regions showed the highest Aβ plaque loads, predominantly consisting of diffuse light and small dense plaques. Plaque densities correlated within and across the hippocampal and cortical regions. Abundances of diffuse dense, small dense, and compact plaques were positively correlated with one another, while densities of cored plaques and CAA did not correlate with other plaque classes. Only cored plaques were positively correlated with the entorhinal tau load, while other plaque classes, except CAA, showed negative correlations. Notably, female sex was associated with more diffuse plaques, and ApoE4 was associated with diffuse dense and small dense plaques. Earlier age at onset and death were associated with higher densities of diffuse light plaques. Overall, associations varied across brain regions and plaque classes. Cored plaques and CAA stand out statistically from other Aβ deposits, suggesting distinct association patterns in the course of the disease.

Keywords:  Alzheimer’s disease; Amyloid beta; Classification; Digital pathology; Machine learning; Plaque morphology

DOI:  https://doi.org/10.1007/s00401-026-03096-1
RSC Adv. 2026 Oct 06.

Design, synthesis, and biological evaluation of naphthalimide derivatives as dual monoamine oxidase-B and amyloid-β aggregation inhibitors for Alzheimer's disease.

Rukshar Praveen, Alessandro Gadaleta, Gabriella La Spada, Daniela Valeria Miniero, Aquib Reza, Tohasib Yusub Chaudhari, Abdur Rahman, Marco Catto, Nasimul Hoda.

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disorder with multifactorial pathogenesis. Amyloid beta (Aβ) and monoamine oxidase (MAO) are among the key therapeutic targets for its treatment. In this investigation, a series of 18 new naphthalimide-based derivatives were synthesized and assessed for multitarget activity against hAChE, esBuChE, MAO-A, MAO-B, Aβ, and paired helical fragment 6 (PHF6) aggregation. The screened compounds predominantly exhibited dual inhibition of MAO-B and Aβ aggregation to counteract oxidative stress and plaque formation. Among the tested compounds, P12 and P17 were found to have remarkable inhibition against Aβ, with 83% and 91% inhibition, respectively, compared to the reference compound quercetin (75% inhibition). The compound P10 was the most effective MAO-B inhibitor, with an IC50 value of 3.09 ± 0.10 µM. Cytotoxicity studies in SH-SY5Y cells confirmed that compounds were non-toxic up to 25 µM. Additionally, the neuroprotection assays revealed that P10 was capable of reducing oxidative stress effectively against H2O2-induced toxicity, while P12 showed superior protection against Aβ-induced neurotoxicity in SH-SY5Y cells. Furthermore, in silico investigations provided structural insights into the predicted ligand-target interaction modes and dynamic behavior of the selected compounds with MAO-B and monomeric Aβ1-42. Consequently, all these findings underscore that naphthalimide derivatives are promising dual inhibitors of amyloid-β aggregation and MAO-B and have potential for further development as MTDLs for AD.

DOI: https://doi.org/10.1039/d6ra07131g
Front Neurosci. 2026 ;20 1913175

Differential autophagy cargo engagement in amyloid-β-induced neuronal toxicity.

Danielle Brink, Rensu Theart, Benjamin Loos.

  Neurodegenerative diseases are characterized by progressive neuronal loss and the accumulation of misfolded proteins. In Alzheimer's disease, several pathogenic protein species, including amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein, are known substrates of macroautophagy. However, the extent to which macroautophagy selectively engages these proteins for degradation under conditions of proteotoxic stress remains poorly understood. Here, the contribution of specifically macroautophagy to the degradation of amyloid precursor protein, amyloid beta, tau, phosphorylated tau, and alpha-synuclein was investigated using an amyloid precursor protein overexpression model. Mouse neuroblastoma N2A cells stably expressing the human Swedish amyloid precursor protein mutation were treated with butyric acid for 24 and 48 h to produce increasing proteotoxicity and molecular pathology. Autophagic flux was assessed using bafilomycin A1 and protein abundance quantified by western blotting. Confocal microscopy and colocalization analysis was performed to examine intracellular protein localization and recruitment to the autophagy compartment. Amyloid precursor protein overexpression and autophagosome/lysosome fusion inhibition elicited distinct protein-specific responses, with phosphorylated tau showing highest accumulation and autophagic recruitment. In contrast, tau and amyloid precursor protein exhibited moderate increases, while alpha-synuclein and amyloid beta showed differential and limited responses upon macroautophagy inhibition. Collectively, these findings suggest that the autophagy molecular machinery does not engage uniformly with Alzheimer's disease-associated proteins but may be characterized by a highly differential cargo engagement under amyloid precursor protein-driven proteotoxic stress. Phosphorylated tau emerged as the earliest and most prominent protein to be target to the autophagy compartment, highlighting its potential importance in disease progression and therapeutic intervention.

Keywords:  Alzheimer's disease; amyloid; autophagy; fluorescence; neurodegenerative disease

DOI:  https://doi.org/10.3389/fnins.2026.1913175
Neuroscience. 2026 Oct 03. pii: S0306-4522(26)00661-5. [Epub ahead of print]

Therapeutic potential of proline-rich peptide-1 (PRP-1) in counteracting amyloid-β-mediated cortical and hippocampal neurodegeneration in a rat model.

Harutyun Stepanyan, Hamzeh Ghorbani, Mikhail Poghosyan, Margarita Danielyan, Arsen Minasyan, Arsen Hunanyan, Naira Hunanyan.

  Alzheimer's disease (AD) is associated with amyloid β (Aβ) accumulation, neuronal metabolic dysfunction, and structural degeneration. This study compares the neurotoxic effects of Aβ25-35 and Aβ1-42 in the rat cerebral cortex and hippocampus and evaluates the neuroprotective potential of proline rich peptide 1 (PRP-1). Amyloid peptides were administered bilaterally into the lateral ventricles, followed by intramuscular PRP-1 at 0.1 mg/kg once daily for three weeks, beginning 24 h after amyloid administration. Neuronal metabolic activity was assessed by Ca2⁺ dependent acid phosphatase histochemistry with a lead capture reaction. Reaction intensity was quantified by densitometry as mean gray value (MGV), with lower values indicating greater reaction product accumulation and higher enzymatic activity. Both amyloid species disrupted cortical laminar organisation and altered enzymatic reactivity in the perikarya and dendrites of cortical pyramidal neurons, with Aβ1-42 causing greater structural disruption. When fields recorded with the same objective were compared, Aβ1-42 produced suppression of enzymatic activity in the hippocampus. CA1 pyramidal neurons showed the highest susceptibility, with confluent areas of reduced reactivity and interruption of the pyramidal cell layer. In the cortex, changes were restricted to the most severely damaged neurons. PRP-1 attenuated these alterations, preserved neuronal morphology, increased the number of reactive neurons, and enhanced enzymatic reactivity in both regions. Protection was greater in the hippocampus. These findings indicate that Aβ1-42 has greater neurotoxicity than Aβ25-35 and that PRP-1 reduces amyloid associated neuronal injury while supporting metabolic and structural recovery. PRP-1 merits further investigation as a candidate therapeutic agent for early amyloid associated neurodegeneration.

Keywords:  Alzheimer’sdisease; Ca2⁺ dependent acid phosphatase; Cerebral cortex; Hippocampus; Proline-richpeptide-1

DOI:  https://doi.org/10.1016/j.neuroscience.2026.09.043
JMA J. 2026 Sep 15. 9(5): 1056-1064

The Amyloid State of Mutant p53 in Cancer.

Naoyuki Iwahashi, Kazuhiko Ino.

  Mutations in TP53, the most frequently altered gene in human cancer, have long been interpreted within a genetic framework centered on loss of tumor-suppressive function and dominant-negative inhibition. Here, we highlight an emerging paradigm in which mutant p53 operates as a protein conformational disease. A growing body of evidence demonstrates that many cancer-associated p53 mutants adopt an amyloid-like state driven by structural destabilization of the DNA-binding domain, exposing aggregation-prone sequences that nucleate β-sheet-rich oligomers and fibrils. These aggregates exhibit prion-like properties, enabling templated misfolding and self-propagation of aberrant p53 conformations within cells. Beyond intracellular accumulation, recent experimental findings suggest that p53 aggregates may be transferred between cells via extracellular vesicles and heparan sulfate proteoglycan-mediated uptake. However, whether such transfer results in sustained tissue-level propagation within human tumors remains to be established. This proposed "seed-and-spread" model provides an emerging conceptual framework for understanding tumor heterogeneity and disease evolution beyond genetic alterations alone. Clinically, amyloid-like p53 aggregates have been detected in multiple malignancies, including ovarian, breast, and lung cancers, where they are associated with aggressive phenotypes, therapeutic resistance, and poor patient outcomes. These observations indicate that the conformational state of p53 represents a critical but previously underappreciated determinant of tumor behavior. Reframing mutant p53 as a self-propagating oncogenic proteinopathy bridges cancer biology with the principles of neurodegenerative disease and opens new therapeutic opportunities. Targeting the aggregation process, restoring native folding, promoting degradation of misfolded p53, or interrupting intercellular transmission may enable direct intervention against TP53-mutant cancers, which account for nearly half of all human malignancies. This perspective establishes protein misfolding and conformational propagation as central drivers of oncogenesis and highlights a new frontier for precision oncology.

Keywords:  cancer; gene mutation; oncology; p53; protein aggregate

DOI:  https://doi.org/10.31662/jmaj.2026-0134