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Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease.

ABSTRACT: Point mutations in the amyloid-? (A?) coding region produce a combination of mutant and WT A? isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant A? determines WT A? conformation through prion template-directed misfolding. Using principal component analysis of multiple structure-sensitive fluorescent amyloid-binding dyes, we assessed the conformational variability of A? deposits in fAD, fCAA, and sAD patients. Comparing many deposits from a given patient with the overall population, we found that intrapatient variability is much lower than interpatient variability for both disease types. In a given brain, we observed one or two structurally distinct forms. When two forms coexist, they segregate between the parenchyma and cerebrovasculature, particularly in fAD patients. Compared with sAD samples, deposits from fAD patients show less intersubject variability, and little overlap exists between fAD and sAD deposits. Finally, we examined whether E22G (Arctic) or E22Q (Dutch) mutants direct the misfolding of WT A?, leading to fAD-like plaques in vivo. Intracerebrally injecting mutant A?40 fibrils into transgenic mice expressing only WT A? induced the deposition of plaques with many biochemical hallmarks of fAD. Thus, mutant A?40 prions induce a conformation of WT A? similar to that found in fAD deposits. These findings indicate that diverse AD phenotypes likely arise from one or more initial A? prion conformations, which kinetically dominate the spread of prions in the brain.

SUBMITTER: Condello C

PROVIDER: S-EPMC5789926 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.

Condello Carlo C Lemmin Thomas T Stöhr Jan J Nick Mimi M Wu Yibing Y Maxwell Alison M AM Watts Joel C JC Caro Christoffer D CD Oehler Abby A Keene C Dirk CD Bird Thomas D TD van Duinen Sjoerd G SG Lannfelt Lars L Ingelsson Martin M Graff Caroline C Giles Kurt K DeGrado William F WF Prusiner Stanley B SB

Proceedings of the National Academy of Sciences of the United States of America 20180108 4

Point mutations in the amyloid-β (Aβ) coding region produce a combination of mutant and WT Aβ isoforms that yield unique clinicopathologies in familial Alzheimer's disease (fAD) and cerebral amyloid angiopathy (fCAA) patients. Here, we report a method to investigate the structural variability of amyloid deposits found in fAD, fCAA, and sporadic AD (sAD). Using this approach, we demonstrate that mutant Aβ determines WT Aβ conformation through prion template-directed misfolding. Using principal co ...[more]

PMID: 29311311

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Project description:Our understanding of Alzheimer's disease pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of the disease. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). Here we reprogrammed primary fibroblasts from two patients with familial Alzheimer's disease, both caused by a duplication of the amyloid-? precursor protein gene (APP; termed APP(Dp)), two with sporadic Alzheimer's disease (termed sAD1, sAD2) and two non-demented control individuals into iPSC lines. Neurons from differentiated cultures were purified with fluorescence-activated cell sorting and characterized. Purified cultures contained more than 90% neurons, clustered with fetal brain messenger RNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APP(Dp) patients and patient sAD2 exhibited significantly higher levels of the pathological markers amyloid-?(1-40), phospho-tau(Thr?231) and active glycogen synthase kinase-3? (aGSK-3?). Neurons from APP(Dp) and sAD2 patients also accumulated large RAB5-positive early endosomes compared to controls. Treatment of purified neurons with ?-secretase inhibitors, but not ?-secretase inhibitors, caused significant reductions in phospho-Tau(Thr?231) and aGSK-3? levels. These results suggest a direct relationship between APP proteolytic processing, but not amyloid-?, in GSK-3? activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial Alzheimer's disease samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to Alzheimer's disease, even though it can take decades for overt disease to manifest in patients.

Dataset Information

Structural heterogeneity and intersubject variability of A? in familial and sporadic Alzheimer's disease.

Publications

Structural heterogeneity and intersubject variability of Aβ in familial and sporadic Alzheimer's disease.

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