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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 w...

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Autores principales: Lilek, Jaclyn, Ajroud, Kaouther, Feldman, Alexander Z., Krishnamachari, Sesha, Ghourchian, Shadi, Gefen, Tamar, Spencer, Callen L., Kawles, Allegra, Mao, Qinwen, Tranovich, Jessica F., Jack, Clifford R., Mesulam, M-Marsel, Reichard, R. Ross, Zhang, Hui, Murray, Melissa E., Knopman, David, Dickson, Dennis W., Petersen, Ronald C., Smith, Benjamin, Ashe, Karen H., Mielke, Michelle M., Nelson, Kathryn M., Flanagan, Margaret E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: IOS Press 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041451/
https://www.ncbi.nlm.nih.gov/pubmed/36744338
http://dx.doi.org/10.3233/JAD-220848
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author Lilek, Jaclyn
Ajroud, Kaouther
Feldman, Alexander Z.
Krishnamachari, Sesha
Ghourchian, Shadi
Gefen, Tamar
Spencer, Callen L.
Kawles, Allegra
Mao, Qinwen
Tranovich, Jessica F.
Jack, Clifford R.
Mesulam, M-Marsel
Reichard, R. Ross
Zhang, Hui
Murray, Melissa E.
Knopman, David
Dickson, Dennis W.
Petersen, Ronald C.
Smith, Benjamin
Ashe, Karen H.
Mielke, Michelle M.
Nelson, Kathryn M.
Flanagan, Margaret E.
author_facet Lilek, Jaclyn
Ajroud, Kaouther
Feldman, Alexander Z.
Krishnamachari, Sesha
Ghourchian, Shadi
Gefen, Tamar
Spencer, Callen L.
Kawles, Allegra
Mao, Qinwen
Tranovich, Jessica F.
Jack, Clifford R.
Mesulam, M-Marsel
Reichard, R. Ross
Zhang, Hui
Murray, Melissa E.
Knopman, David
Dickson, Dennis W.
Petersen, Ronald C.
Smith, Benjamin
Ashe, Karen H.
Mielke, Michelle M.
Nelson, Kathryn M.
Flanagan, Margaret E.
author_sort Lilek, Jaclyn
collection PubMed
description 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.
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spelling pubmed-100414512023-03-28 Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease Lilek, Jaclyn Ajroud, Kaouther Feldman, Alexander Z. Krishnamachari, Sesha Ghourchian, Shadi Gefen, Tamar Spencer, Callen L. Kawles, Allegra Mao, Qinwen Tranovich, Jessica F. Jack, Clifford R. Mesulam, M-Marsel Reichard, R. Ross Zhang, Hui Murray, Melissa E. Knopman, David Dickson, Dennis W. Petersen, Ronald C. Smith, Benjamin Ashe, Karen H. Mielke, Michelle M. Nelson, Kathryn M. Flanagan, Margaret E. J Alzheimers Dis Research Article 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. IOS Press 2023-03-07 /pmc/articles/PMC10041451/ /pubmed/36744338 http://dx.doi.org/10.3233/JAD-220848 Text en © 2023 – The authors. Published by IOS Press https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial (CC BY-NC 4.0) License (https://creativecommons.org/licenses/by-nc/4.0/) , which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Article
Lilek, Jaclyn
Ajroud, Kaouther
Feldman, Alexander Z.
Krishnamachari, Sesha
Ghourchian, Shadi
Gefen, Tamar
Spencer, Callen L.
Kawles, Allegra
Mao, Qinwen
Tranovich, Jessica F.
Jack, Clifford R.
Mesulam, M-Marsel
Reichard, R. Ross
Zhang, Hui
Murray, Melissa E.
Knopman, David
Dickson, Dennis W.
Petersen, Ronald C.
Smith, Benjamin
Ashe, Karen H.
Mielke, Michelle M.
Nelson, Kathryn M.
Flanagan, Margaret E.
Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title_full Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title_fullStr Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title_full_unstemmed Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title_short Accumulation of pTau231 at the Postsynaptic Density in Early Alzheimer’s Disease
title_sort accumulation of ptau231 at the postsynaptic density in early alzheimer’s disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10041451/
https://www.ncbi.nlm.nih.gov/pubmed/36744338
http://dx.doi.org/10.3233/JAD-220848
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