Important progress in understanding Alzheimer's disease!

▎WuXi AppTec Content Team Editor The top academic journal Science recently published an important paper on Alzheimer's disease (AD)
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Using cryo-electron microscopy (Cryo-EM) technology, researchers from Indiana University in the US and the MRC Laboratory of Molecular Biology in the UK have collaborated to unravel a major mystery surrounding the pathogenesis of Alzheimer's disease: in patients' brains , How the fibrillar structure of the β-amyloid peptide chain (Aβ42) is formed
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News from the research institute states that this study provides the first high-resolution structure of Aβ42 protein fibrils derived from human brain tissue
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The new structure identifies two filament types of Aβ42 that do not assemble in the same way as seen in in vitro experiments in the past
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The journal "Science" specifically commented on the study, which attracted a lot of attention
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Mathias Jucker from the German Center for Neurodegenerative Diseases and other experts in related fields commented: "The first author Dr.
Yang Yang and his colleagues have provided gorgeous and informative cryo-EM images of Aβ aggregates, which is an important step
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" Two types of Aβ42 filament structures resolved in the tissue: type I (left) and type II (right) (Image source: Reference [3]) In the entire cerebral cortex of patients with Alzheimer's disease, a large amount of Aβ is formed.
Amyloid plaques are a hallmark feature
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Some evidence suggests that Aβ deposition is a key driver of Alzheimer's disease
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Among the Aβ fragments of different sizes, Aβ42 is considered to be the most neurotoxic, and its increased aggregation and deposition are associated with age
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In this study, the scientists obtained brain tissue samples from the remains of 10 patients with neurodegenerative diseases, of which 3 had episodic AD, 2 had familial AD, and 5 were associated with amyloid deposition.
other diseases
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The researchers isolated fibrils from plaques composed primarily of Aβ42 and performed high-resolution structural analysis
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The analysis found two types of S-folded fibrils, from which two different types of Aβ42 filaments were generated
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Both types of protein filaments consist of pairs of two fibrils, but twist in different ways
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Among them, type I filaments mainly appear in sporadic AD cases, and type II filaments predominate in familial AD cases and also appear in other cases
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The researchers also analyzed Aβ deposits extracted from the brains of mice that mimic familial Alzheimer's, knocked in the human disease-causing gene AppNL-F, and also have type II filaments
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The researchers pointed out that this experimental system provides an amyloid filament structure similar to that of the human brain, which is helpful for subsequent studies to further explore the aggregation mechanism of Aβ filaments
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▲The peptide conformation of Aβ42 fibrils found in human brain tissue is different from that of Aβ40 fibrils.
Aβ42 is S-shaped at the carboxyl terminus, and Aβ40 is C-shaped (Image source: Reference [2]) Based on the above results, the research team pointed out that, This study significantly improves our understanding of Alzheimer's disease pathogenesis and could open the way for the development of more sensitive and specific imaging agents
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In addition, designing compounds that can inhibit Aβ42 assembly may also lead to a viable new therapeutic strategy for Alzheimer's disease
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Source of title map: 123RF References: [1] Yang Yang et al.
, (2022) Cryo-EM structures of amyloid-β 42 filaments from human brain.
Science.
Doi: 10.
1126/science.
abm7285[2] Michael Willem & Marcus Fandrich (2022) A molecular view of human amyloid-β folds.
Science.
DOI: 10.
1126/science.
abn5428[3] Atomic structures of Aβ42 filaments from the brains of individuals with Alzheimer's disease and other neurodegenerative conditions.
Retrieved Jan.
18, 2022 from https://www2.
mrc-lmb.
cam.
ac.
uk/atomic-structures-of-a%ce%b242-filaments-from-the-brains-of-individuals-with-alzheimers-disease-and-other -neurodegenerative-conditions/[4] Cryo-EM Unveils Distinct Aβ42 Fibril Structures for Sporadic, Familial AD.
Retrieved Jan.
18, 2022 from https:// -distinct-av42-fibril-structures-sporadic-familial-ad