Synaptic Loss, ER Stress and Neuro-Inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer\u2019s Disease

Heather Buchanan,Karolína Tothová,Murray Mackay,David J Koss,Miroslava Katsur,Kerri Palmer,Bettina Platt

doi:10.1007/s12035-020-01950-1

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.

Highlights

Alzheimer’s disease (AD), the most common cause of dementia, is characterised by the accumulation of extracellularElectronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau
Our data suggest that specific synaptic, endoplasmic reticulum (ER) stress and neuro-inflammatory markers are affected in late AD in the temporal gyrus
Given that our previous analysis of temporal cortical tau and Aβ pathology within the same cohort has demonstrated the co-localisation of soluble Aβ and tau pathology at intermediate stages of neuropathological severity (Braak NFT stages 2–3), the pathways studied here do not precede the spread of tau or Aβ pathology and are likely secondary events

Summary

Introduction

Amyloid-β (Aβ) containing plaques and intracellular neurofibrillary tangles (NFTs) composed of hyper-phosphorylated tau. These hallmark features have largely been the focus of AD research; for decades, the ‘amyloid cascade hypothesis’ [1] remained the foremost pathogenic concept in the field and has since been revised to incorporate a role for earlier occurring soluble species, which appear to hold more disease relevance [2,3,4]. After consistent failures in clinical trials, we are still without a disease-modifying agent [5]. This has called into question the validity of current hypotheses and our conceptual understanding of disease aetiology.

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