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Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease

Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease Background:Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear.Objective:To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD.Methods:Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X.Results:Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization.Conclusion:Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Alzheimer's Disease IOS Press

Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease

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References (62)

Publisher
IOS Press
Copyright
© 2023 – The authors. Published by IOS Press
ISSN
1387-2877
eISSN
1875-8908
DOI
10.3233/jad-220848
Publisher site
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Abstract

Background:Phosphorylated cytoplasmic tau inclusions correlate with and precede cognitive deficits in Alzheimer’s disease (AD). However, pathological tau accumulation and relationships to synaptic changes remain unclear.Objective:To address this, we examined postmortem brain from 50 individuals with the full spectrum of AD (clinically and neuropathologically). Total tau, pTau231, and AMPA GluR1 were compared across two brain regions (entorhinal and middle frontal cortices), as well as clinically stratified groups (control, amnestic mild cognitive impairment, AD dementia), NIA-AA Alzheimer’s Disease Neuropathologic Change designations (Not, Low, Intermediate, High), and Braak tangle stages (1–6). Significant co-existing pathology was excluded to isolate changes attributed to pathologic AD.Methods:Synaptosomal fractionation and staining were performed to measure changes in total Tau, pTau231, and AMPA GluR1. Total Tau and pTau231 were quantified in synaptosomal fractions using Quanterix Simoa HD-X.Results:Increasing pTau231 in frontal postsynaptic fractions correlated positively with increasing clinical and neuropathological AD severity. Frontal cortex is representative of early AD, as it does not become involved by tau tangles until late in AD. Entorhinal total tau was significantly higher in the amnestic mild cognitive impairment group when compared to AD, but only after accounting for AD associated synaptic changes. Alterations in AMPA GluR1 observed in the entorhinal cortex, but not middle frontal cortex, suggest that pTau231 mislocalization and aggregation in postsynaptic structures may impair glutamatergic signaling by promoting AMPA receptor dephosphorylation and internalization.Conclusion:Results highlight the potential effectiveness of early pharmacological interventions targeting pTau231 accumulation at the postsynaptic density.

Journal

Journal of Alzheimer's Disease – IOS Press

Published: Mar 7, 2023

Keywords: Alzheimer’s disease; cognitive impairment; phosphorylated tau; PSD-95; Simoa Quanterix; synaptic dysfunction; synaptophysin; tau

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