DOI: 10.1002/alz.075661 ISSN: 1552-5260

3. Neuropathological differences between Down syndrome and familial Alzheimer’s disease with APP duplication: role of endothelial cells in cerebral amyloid angiopathy.

Marie‐Claude Potier
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Geriatrics and Gerontology
  • Neurology (clinical)
  • Developmental Neuroscience
  • Health Policy
  • Epidemiology



While amyloid plaques are common in all AD cases, CAA is mainly found in familial AD with duplications of the APP gene (DUP‐APP), Down Syndrome (DS), and specific APP mutations. Mechanisms leading to these differences are not yet understood. We investigated the diversity of neuropathological phenotypes and the composition of brain Aß peptides in sporadic AD (sAD), DUP‐APP, APP mutations, DS with or without dementia (D), and control cases. In addition, we analysed endothelial cells derived from iPSC lines (iPSC‐d‐ECs) of patients to model the vessel wall forming the blood‐brain barrier.


We analyzed Aβ and Tau pathologies in post‐mortem human brain tissues by immunohistochemistry on paraffin‐embedded sections (12 sAD, 7 DUP‐APP, 3 DS, 10 DS‐D and 9 APP mutations cases). Using immunoprecipitation and mass spectrometry, we characterized Aß species in brain homogentes from the same cases. We analysed the morphology of iPSCs‐d‐ECs, measured their levels of Aβ secretion and junctional proteins and analysed their transcriptomes.


Aβ deposits in the parenchyma were found in sAD, DS‐D and APP mutations, and less abundant in DUP‐APP. Conversely, Aβ deposits in the blood vessels (arteries and arterioles) were prominent in DUP‐APP, less abundant in DS‐D and even less frequent in sAD and APP mutations. Only DUP‐APP cases showed Aβ deposits in the capillaries. Despite striking differences in Aβ pathologies, all cases with dementia had high Tau pathology. Aß peptides signatures were different in cases with CAA, with higher levels of shorter Aß peptides and truncated species at position 2 at the N‐terminus. iPSC‐d‐ECs secreted substantial amounts of Aβ peptides. We identified changes in the morphology and tight junctions of iPSC‐d‐ECs with DUP‐APP as well as specific gene expression dysregulations, suggesting intrinsic remodelling of ECs of the blood‐brain barrier in DUP‐APP.


Our study reveals new pathophysiological mechanisms involved in specific Aβ production and deposition in the blood vessel wall of patients carrying DUP‐APP involving EC. Differences between DUP‐APP and DS suggest the presence in the DS population of protective factors against CAA.

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