Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease

Mitsuru Shinohara, Shinsuke Fujioka, Melissa E Murray, Aleksandra Wojtas, Matthew Baker, Anne Rovelet-Lecrux, Rosa V Rademakers, Pritam Das, Joseph E Parisi, Neill R Graff Radford, Ronald Carl Petersen, Dennis W Dickson, Guojun D Bu

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Abstract

Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-β accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 ± 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 ± 7.8 years), neurologically normal elderly without amyloid-β accumulation (normal ageing; n = 13, age at death: 82.9 ± 10.8 years) and neurologically normal elderly with extensive cortical amyloid-β deposits (pathological ageing; n = 15; age at death: 92.7 ± 5.9 years). The levels of amyloid-β40, amyloid-β42, APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-β metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-β42 accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid- β42 accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-β metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-β metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-β42 accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as β-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-β42 accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-β (especially amyloid-β40) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-β42 accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-β42 accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-β42 accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)1533-1549
Number of pages17
JournalBrain
Volume137
Issue number5
DOIs
StatePublished - 2014

Fingerprint

Amyloid beta-Protein Precursor
Amyloid
Alzheimer Disease
Alzheimer's Disease
Familial
Protein
Precursor
Apolipoproteins E
Presenilin-1
Corpus Striatum
Mutation
Clinical Pathology
Amyloid Plaques
Brain

Keywords

  • Alzheimer's disease
  • amyloid-β
  • APP
  • neuroanatomy
  • synapses

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer's disease. / Shinohara, Mitsuru; Fujioka, Shinsuke; Murray, Melissa E; Wojtas, Aleksandra; Baker, Matthew; Rovelet-Lecrux, Anne; Rademakers, Rosa V; Das, Pritam; Parisi, Joseph E; Graff Radford, Neill R; Petersen, Ronald Carl; Dickson, Dennis W; Bu, Guojun D.

In: Brain, Vol. 137, No. 5, 2014, p. 1533-1549.

Research output: Contribution to journalArticle

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AU - Baker, Matthew

AU - Rovelet-Lecrux, Anne

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AU - Dickson, Dennis W

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