Dataset Information

Amyloid ?-Protein Assembly and Alzheimer's Disease: Dodecamers of A?42, but Not of A?40, Seed Fibril Formation.

ABSTRACT: Evidence suggests that oligomers of the 42-residue form of the amyloid ?-protein (A?), A?42, play a critical role in the etiology of Alzheimer's disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of A?42 that occur at the earliest stages of aggregation. We observe features that can be attributed to a monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that A?42 hexamers and dodecamers quickly become the dominant oligomers after peptide solubilization, even at low (1 ?M) concentrations and short (5 min) incubation times. Soon after (?10 min), dodecamers are observed to seed the formation of extended, linear preprotofibrillar ?-sheet structures. The preprotofibrils are a single A?42 layer in height and can extend several hundred nanometers in length. To our knowledge this is the first report of structures of this type. In each instance the preprotofibril is associated off center with a single layer of a dodecamer. Protofibril formation continues at longer times, but is accompanied by the formation of large, globular aggregates. A?40, by contrast, does not significantly form the hexamer or dodecamer but instead produces a mixture of smaller oligomers. These species lead to the formation of a branched chain-like network rather than discrete structures.

SUBMITTER: Economou NJ

PROVIDER: S-EPMC4849547 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

Amyloid β-Protein Assembly and Alzheimer's Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation.

Economou Nicholas J NJ Giammona Maxwell J MJ Do Thanh D TD Zheng Xueyun X Teplow David B DB Buratto Steven K SK Bowers Michael T MT

Journal of the American Chemical Society 20160204 6

Evidence suggests that oligomers of the 42-residue form of the amyloid β-protein (Aβ), Aβ42, play a critical role in the etiology of Alzheimer's disease (AD). Here we use high resolution atomic force microscopy to directly image populations of small oligomers of Aβ42 that occur at the earliest stages of aggregation. We observe features that can be attributed to a monomer and to relatively small oligomers, including dimers, hexamers, and dodecamers. We discovered that Aβ42 hexamers and dodecamers ...[more]

PMID: 26839237

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Project description:BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer's disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T - = 98) or pathological p-tau levels (A + T + = 65) and 36 control subjects (A - T -). A + T - patients were further stratified into those with normal (CSFAβ42 + /amyR - = 46) and pathological amyR (CSFAβ42 + /amyR + = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A - T - and in CSFAβ42 + /amyR - , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A - T - (β = 0.58; p < 0.001), CSFAβ42 + /amyR - (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR - (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A - T - . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR - compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.

Dataset Information

Amyloid ?-Protein Assembly and Alzheimer's Disease: Dodecamers of A?42, but Not of A?40, Seed Fibril Formation.

Publications

Amyloid β-Protein Assembly and Alzheimer's Disease: Dodecamers of Aβ42, but Not of Aβ40, Seed Fibril Formation.

Similar Datasets

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