[Neurosciences/Alzheimer] Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes

Interesting study published in Nature about how differences in Abeta fibrils have an implication on the clinical symptoms.
A quick refresher for those not much familiar (it is also a bit of a headache as I just dive in the Alzheimer’s research). Alzheimer’s disease is characterized by the formation of senile plaques and tangles, such structures have been considered as the causative agents in neuronal cell death.
These plaques are clumps of a peptide called Abeta (for amyloid beta) peptides. We know how these peptides are formed (by cleavage of the amyloid precursor protein or APP) and we know there are different “flavors” of Abeta that have been described: Abeta 1-40, Abeta 1-42…..
We also know that these peptides are “sticky”. They are released as monomers (single peptide) and because they are hydrophobic (hates water, like oil hates water) they will try to bind together and form oligomers (think about little sticky balls). These oligomers then can form fibrils.
It is a very “dry” study because it is heavy on structural biology and computational biology but in the same time very interesting.
It shows us that plaque formation is not a linear processes, there are different combinations possible (imagine like comparing snowflakes) that have a direct impact on the clinical presentation and outcomes in patients.
That’s maybe providing another way of thinking in targeting Abeta that can help us learn from the failure of previous clinical trials.

Abstract and link to the original paper

Aggregation of amyloid-β peptides into fibrils or other self-assembled states is central to the pathogenesis of Alzheimer’s disease. Fibrils formed in vitro by 40- and 42-residue amyloid-β peptides (Aβ40 and Aβ42) are polymorphic, with variations in molecular structure that depend on fibril growth conditions. Recent experiments suggest that variations in amyloid-β fibril structure in vivo may correlate with variations in Alzheimer’s disease phenotype, in analogy to distinct prion strains that are associated with different clinical and pathological phenotypes. Here we investigate correlations between structural variation and Alzheimer’s disease phenotype using solid-state nuclear magnetic resonance (ssNMR) measurements on Aβ40 and Aβ42 fibrils prepared by seeded growth from extracts of Alzheimer’s disease brain cortex. We compared two atypical Alzheimer’s disease clinical subtypes—the rapidly progressive form (r-AD) and the posterior cortical atrophy variant (PCA-AD)—with a typical prolonged-duration form (t-AD). On the basis of ssNMR data from 37 cortical tissue samples from 18 individuals, we find that a single Aβ40 fibril structure is most abundant in samples from patients with t-AD and PCA-AD, whereas Aβ40 fibrils from r-AD samples exhibit a significantly greater proportion of additional structures. Data for Aβ42 fibrils indicate structural heterogeneity in most samples from all patient categories, with at least two prevalent structures. These results demonstrate the existence of a specific predominant Aβ40 fibril structure in t-AD and PCA-AD, suggest that r-AD may relate to additional fibril structures and indicate that there is a qualitative difference between Aβ40 and Aβ42 aggregates in the brain tissue of patients with Alzheimer’s disease.

Source: Structural variation in amyloid-β fibrils from Alzheimer’s disease clinical subtypes : Nature : Nature Research


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