Dataset Information

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis.

ABSTRACT: The hippocampus is a primary region affected in Alzheimer's disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis by comparing patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of pathways and network dysfunction in AD patient brain cells, associated with increased levels of Aβ-42 and β-sheet structures. Interestingly, the host cells surrounding the AD graft also presented alterations in cellular biological pathways. Furthermore, proteomic analysis across human iPSC-based models and human post-mortem hippocampal tissue projected coherent longitudinal cellular changes indicative of early to end stage AD cellular pathogenesis. Our data showcase patient-based models to study the cell autonomous origin and progression of AD pathogenesis.

SUBMITTER: Pomeshchik Y

PROVIDER: S-EPMC10504768 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis.

Pomeshchik Yuriy Y Velasquez Erika E Gil Jeovanis J Klementieva Oxana O Gidlöf Ritha R Sydoff Marie M Bagnoli Silvia S Nacmias Benedetta B Sorbi Sandro S Westergren-Thorsson Gunilla G Gouras Gunnar K GK Rezeli Melinda M Roybon Laurent L

Acta neuropathologica communications 20230915 1

The hippocampus is a primary region affected in Alzheimer's disease (AD). Because AD postmortem brain tissue is not available prior to symptomatic stage, we lack understanding of early cellular pathogenic mechanisms. To address this issue, we examined the cellular origin and progression of AD pathogenesis by comparing patient-based model systems including iPSC-derived brain cells transplanted into the mouse brain hippocampus. Proteomic analysis of the graft enabled the identification of pathways ...[more]

PMID: 37715247

Similar Datasets

Project description:BackgroundPost-mortem studies have not identified an association between β-amyloid or tau and rates of hippocampal atrophy in patients with Alzheimer's disease. TAR DNA binding protein 43 (TDP-43) is another protein linked to Alzheimer's disease. We aimed to investigate whether hippocampal TDP-43 is associated with increased rates of hippocampal atrophy.MethodsIn this longitudinal retrospective study, we analysed post-mortem brain tissue of all individuals with an Alzheimer's disease spectrum pathological diagnosis who had antemortem head MRI scans between Jan 1, 1999, and Dec 31, 2012, and who had been recruited into the Mayo Clinic Alzheimer's Disease Research Center, Mayo Clinic Alzheimer's Disease Patient Registry, or the Mayo Clinic Study of Aging. We did TDP-43 immunohistochemistry and classified individuals as follows: no TDP-43 in the amygdala or hippocampus; TDP-43 restricted to the amygdala; and TDP-43 spreading into the hippocampus. Each individual was also assigned a neurofibrillary tangle stage (B1-B3), relating to the likelihood of having Alzheimer's disease. We used longitudinal FreeSurfer software and tensor-based morphometry with symmetric normalisation to calculate hippocampal volume on all serial MRI scans and used linear mixed-effects regression models to estimate associations between TDP-43 and rate of hippocampal atrophy and to assess the trajectory of TDP-43-associated atrophy.FindingsWe identified 298 individuals meeting the inclusion criteria, with 816 usable MRI scans (spanning 1·0-11·2 years of the disease) available for analysis. 141 individuals showed no TDP-43 in the amygdala or hippocampus, 33 had TDP-43 restricted to the amygdala, and 124 had TDP-43 in the hippocampus. Among individuals with a high likelihood of having Alzheimer's disease (neurofibrillary tangle stage B3; n=205), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=103, annual volume change -4·39%, 95% CI -4·82 to -3·95; p<0·0001) than did those with amygdala-only TDP-43 (n=20, -3·29%, -4·11 to -2·46; p<0·0001; difference -1·10%, 95% CI -2·02 to -0·19; p=0·02) and those without TDP-43 (n=82, -3·11%, -3·54 to -2·68; p<0·0001; difference -1·28%, -1·88 to -0·67; p<0·0001). Among individuals with an intermediate likelihood of having Alzheimer's disease (neurofibrillary tangle stage B2; n=56), those with hippocampal TDP-43 had faster rates of hippocampal atrophy (n=17, annual volume change -4·05%, 95% CI -5·09 to -2·99; p<0·0001) than did those with amygdala-only TDP-43 (n=6, -1·78%, -3·04 to -0·55; p=0·004; difference -2·27%, 95% CI -3·79 to -0·67; p=0·006) and those without TDP-43 (n=33, -1·63%, -2·43 to -0·83; p=0·0002; difference -2·43%, -3·66 to -1·18; p=0·0002). Hippocampal TDP-43 was not associated with the rate of hippocampal atrophy in individuals with a low likelihood of having Alzheimer's disease (neurofibrillary tangle stage B1; n=37). The trajectory analysis suggested that increased rates of TDP-43-associated hippocampal atrophy might occur at least 10 years before death. Results were similar for FreeSurfer and tensor-based morphometry.InterpretationTDP-43 should be considered as a potential factor related to increased rates of hippocampal atrophy in patients with Alzheimer's disease. Given the importance of hippocampal atrophy in Alzheimer's disease, it is imperative that techniques are developed for detection of TDP-43 in vivo.FundingUS National Institute on Aging (National Institutes of Health).

Dataset Information

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis.

Publications

Proteomic analysis across patient iPSC-based models and human post-mortem hippocampal tissue reveals early cellular dysfunction and progression of Alzheimer's disease pathogenesis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets