Synaptic Loss, ER Stress and Neuro-inflammation Emerge Late in the Lateral Temporal Cortex and Associate with Progressive Tau Pathology in Alzheimer’s Disease

Heather Buchanan, Murray Mackay, Kerri Palmer, Karolína Tothová, Miroslava Katsur, Bettina Platt* (Corresponding Author), David J. Koss* (Corresponding Author)

*Corresponding author for this work

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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 languageEnglish
Pages (from-to)3258-3272
Number of pages15
JournalMolecular Neurobiology
Volume57
Early online date8 Jun 2020
DOIs
Publication statusPublished - Aug 2020

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

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