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Diversity in A? deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis.

ABSTRACT: A hallmark pathology of Alzheimer's disease (AD) is the formation of amyloid ? (A?) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic A? morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the transgene constructs that are expressed; including the species origin of A? peptides, the levels and length of A? that is deposited, and whether mutant presenilin 1 (PS1) is co-expressed. These models recapitulate features of human AD amyloidosis, but interestingly some models can produce pathology in which one type of A? morphology dominates. In prior studies of mice that primarily develop cored-neuritic deposits, we determined that A? deposition is associated with changes in cytosolic protein solubility in which a subset of proteins become detergent-insoluble, indicative of secondary proteome instability. Here, we survey changes in cytosolic protein solubility across seven different transgenic mouse models that exhibit a range of A? deposit morphologies. We find a surprisingly diverse range of changes in proteome solubility across these models. Mice that deposit human A?40 and A?42 in cored-neuritic plaques had the most robust changes in proteome solubility. Insoluble cytosolic proteins were also detected in the brains of mice that develop diffuse A?42 deposits but to a lesser extent. Notably, mice with cored deposits containing only A?42 had relatively few proteins that became detergent-insoluble. Our data provide new insight into the diversity of biological effects that can be attributed to different types of A? pathology and support the view that fibrillar cored-neuritic plaque pathology is the more disruptive A? pathology in the Alzheimer's cascade.

SUBMITTER: Xu G

PROVIDER: S-EPMC7137436 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Diversity in Aβ deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis.

Xu Guilian G Fromholt Susan E SE Chakrabarty Paramita P Zhu Fanchao F Liu Xuefei X Pace Michael C MC Koh Jin J Golde Todd E TE Levites Yona Y Lewis Jada J Borchelt David R DR

Acta neuropathologica communications 20200406 1

A hallmark pathology of Alzheimer's disease (AD) is the formation of amyloid β (Aβ) deposits that exhibit diverse localization and morphologies, ranging from diffuse to cored-neuritic deposits in brain parenchyma, with cerebral vascular deposition in leptomeningeal and parenchymal compartments. Most AD brains exhibit the full spectrum of pathologic Aβ morphologies. In the course of studies to model AD amyloidosis, we have generated multiple transgenic mouse models that vary in the nature of the ...[more]

PMID: 32252825

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Project description:BackgroundAlzheimer's disease (AD), the most common cause of dementia, is characterized by the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles. Mouse models of Aβ amyloidosis generated by knock-in (KI) of a humanized Aβ sequence provide distinct advantages over traditional transgenic models that rely on overexpression of amyloid precursor protein (APP). In App-KI mice, three familial AD-associated mutations were introduced into the endogenous mouse App locus to recapitulate Aβ pathology observed in AD: the Swedish (NL) mutation, which elevates total Aβ production; the Beyreuther/Iberian (F) mutation, which increases the Aβ42/Aβ40 ratio; and the Arctic (G) mutation, which promotes Aβ aggregation. AppNL-G-F mice harbor all three mutations and develop progressive Aβ amyloidosis and neuroinflammatory response in broader brain areas, whereas AppNL mice carrying only the Swedish mutation exhibit no overt AD-related pathological changes. To identify behavioral alterations associated with Aβ pathology, we assessed emotional and cognitive domains of AppNL-G-F and AppNL mice at different time points, using the elevated plus maze, contextual fear conditioning, and Barnes maze tasks.ResultsAssessments of emotional domains revealed that, in comparison with wild-type (WT) C57BL/6J mice, AppNL-G-F/NL-G-F mice exhibited anxiolytic-like behavior that was detectable from 6 months of age. By contrast, AppNL/NL mice exhibited anxiogenic-like behavior from 15 months of age. In the contextual fear conditioning task, both AppNL/NL and AppNL-G-F/NL-G-F mice exhibited intact learning and memory up to 15-18 months of age, whereas AppNL-G-F/NL-G-F mice exhibited hyper-reactivity to painful stimuli. In the Barnes maze task, AppNL-G-F/NL-G-F mice exhibited a subtle decline in spatial learning ability at 8 months of age, but retained normal memory functions.ConclusionAppNL/NL and AppNL-G-F/NL-G-F mice exhibit behavioral changes associated with non-cognitive, emotional domains before the onset of definitive cognitive deficits. Our observations consistently indicate that AppNL-G-F/NL-G-F mice represent a model for preclinical AD. These mice are useful for the study of AD prevention rather than treatment after neurodegeneration.

Dataset Information

Diversity in A? deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis.

Publications

Diversity in Aβ deposit morphology and secondary proteome insolubility across models of Alzheimer-type amyloidosis.

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