Abstract
The complex multifactorial nature of AD pathogenesis has been highlighted by evidence implicating additional neurodegenerative mechanisms, beyond that of amyloid-β (Aβ) and tau. To provide insight into cause and effect, we here investigated the temporal profile and associations of pathological changes in synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers. Quantifications were established via immunoblot and immunohistochemistry protocols in post-mortem lateral temporal cortex (n = 46). All measures were assessed according to diagnosis (non-AD vs. AD), neuropathological severity (low (Braak ≤ 2) vs. moderate (3–4) vs. severe (≥ 5)) and individual Braak stage, and were correlated with Aβ and tau pathology and cognitive scores. Postsynaptic PSD-95, but not presynaptic synaptophysin, was decreased in AD cases and demonstrated a progressive decline across disease severity and Braak stage, yet not with cognitive scores. Of all investigated ER stress markers, only phospho-protein kinase RNA-like ER kinase (p-PERK) correlated with Braak stage and was increased in diagnosed AD cases. A similar relationship was observed for the astrocytic glial fibrillary acidic protein (GFAP); however, the associated aquaporin 4 and microglial Iba1 remained unchanged. Pathological alterations in these markers preferentially correlated with measures of tau over those related to Aβ. Notably, GFAP also correlated strongly with Aβ markers and with all assessments of cognition. Lateral temporal cortex-associated synaptic, ER stress and neuro-inflammatory pathologies are here determined as late occurrences in AD progression, largely associated with tau pathology. Moreover, GFAP emerged as the most robust indicator of disease progression, tau/Aβ pathology, and cognitive impairment.
| Original language | English |
|---|---|
| Pages (from-to) | 3258-3272 |
| Number of pages | 15 |
| Journal | Molecular Neurobiology |
| Volume | 57 |
| Early online date | 8 Jun 2020 |
| DOIs | |
| Publication status | Published - Aug 2020 |
Bibliographical note
AcknowledgementsWe would like to deeply thank all donors and their families for the tissue provided for this study. Human tissue samples were supplied by the Brains for Dementia Research programme, jointly funded by Alzheimer’s Research UK, the Alzheimer’s Society and the Medical Research Council, and sourced from the MRC London Neurodegenerative Diseases Brain Bank, the Manchester Brain Bank, the South West Dementia Brain Bank (SWDBB), the Newcastle Brain Tissue Resource and the Oxford Brain Bank. The Newcastle Brain Tissue Resource and Oxford Brain Bank are also supported by the National Institute for Health Research (NIHR) Units. The South West Dementia Brain Bank (SWDBB) receives additional support from BRACE (Bristol Research into Alzheimer’s and Care of the Elderly). Use of human tissue for this work was approved by Brains for Dementia Research from London – City and East NRES committee 08/H0704/128+5. The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUK-PPG2014A-21, ARUK-NSG2015-1, ARUK-NCG2017A-3 awarded to DK and BP). HB was supported by an Alzheimer’s Society Doctoral Training Centre grant (grant ref: 228) to BP. MK’s participation in the project was funded by ARUK Scotland Network pump priming award to DK and BP. Antibodies CP13 and PHF1 were generously provided by Prof. Peter Davies. TOC1 antibodies were a gift from Nicholas Kanaan at Michigan State University (originally created by Lester Binder at Northwestern University).
Funding
The work presented here was funded by Alzheimer’s Research UK (Grant refs: ARUK-PPG2014A-21, ARUK-NSG2015-1, ARUK-NCG2017A-3 awarded to DK and BP). HB was supported by an Alzheimer’s Society Doctoral Training Centre grant (grant ref:228) to BP. MK’s participation in the project was funded by ARUK Scotland Network pump priming award to DK and BP.
Keywords
- Alzheimer's disease
- tau
- amyloid
- Synapse
- unfolded protein response
- neuroinflammation
- Neuro-inflammation
- HUMAN BRAIN
- PHOSPHORYLATION
- TRANSGENIC MOUSE
- Tau
- AMYLOID-BETA-PROTEIN
- ENDOPLASMIC-RETICULUM STRESS
- MODEL
- Unfolded protein response
- COGNITIVE DECLINE
- UNFOLDED PROTEIN RESPONSE
- EIF2-ALPHA
- EXPRESSION
- Amyloid-beta
- Alzheimer’s disease
- Amyloid-β
Access to Document
- Buchanan_etal_MN_SynapticLossERStressAndNeuro_VOR
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.