Amyloid-β peptide signature associated with cerebral amyloid angiopathy in familial Alzheimer’s disease with APPdup and Down syndrome

Amal Kasri, Elena Camporesi, Eleni Gkanatsiou, Susana Boluda, Gunnar Brinkmalm, Lev Stimmer, Junyue Ge, Jörg Hanrieder, Nicolas Villain, Charles Duyckaerts, Yannick Vermeiren, Sarah E. Pape, Gaël Nicolas, Annie Laquerrière, Peter Paul De Deyn, David Wallon, Kaj Blennow, Andre Strydom, Henrik Zetterberg*, Marie Claude Potier*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Alzheimer’s disease (AD) is characterized by extracellular amyloid plaques containing amyloid-β (Aβ) peptides, intraneuronal neurofibrillary tangles, extracellular neuropil threads, and dystrophic neurites surrounding plaques composed of hyperphosphorylated tau protein (pTau). Aβ can also deposit in blood vessel walls leading to cerebral amyloid angiopathy (CAA). While amyloid plaques in AD brains are constant, CAA varies among cases. The study focuses on differences observed between rare and poorly studied patient groups with APP duplications (APPdup) and Down syndrome (DS) reported to have higher frequencies of elevated CAA levels in comparison to sporadic AD (sAD), most of APP mutations, and controls. We compared Aβ and tau pathologies in postmortem brain tissues across cases and Aβ peptides using mass spectrometry (MS). We further characterized the spatial distribution of Aβ peptides with MS-brain imaging. While intraparenchymal Aβ deposits were numerous in sAD, DS with AD (DS-AD) and AD with APP mutations, these were less abundant in APPdup. On the contrary, Aβ deposits in the blood vessels were abundant in APPdup and DS-AD while only APPdup cases displayed high Aβ deposits in capillaries. Investigation of Aβ peptide profiles showed a specific increase in Aβx-37, Aβx-38 and Aβx-40 but not Aβx-42 in APPdup cases and to a lower extent in DS-AD cases. Interestingly, N-truncated Aβ2-x peptides were particularly increased in APPdup compared to all other groups. This result was confirmed by MS-imaging of leptomeningeal and parenchymal vessels from an APPdup case, suggesting that CAA is associated with accumulation of shorter Aβ peptides truncated both at N- and C-termini in blood vessels. Altogether, this study identified striking differences in the localization and composition of Aβ deposits between AD cases, particularly APPdup and DS-AD, both carrying three genomic copies of the APP gene. Detection of specific Aβ peptides in CSF or plasma of these patients could improve the diagnosis of CAA and their inclusion in anti-amyloid immunotherapy treatments.

Original languageEnglish
Article number8
Number of pages19
JournalActa Neuropathologica
Volume148
DOIs
Publication statusPublished - 18 Jul 2024

Keywords

  • Alzheimer’s disease
  • Aβ peptides
  • Cerebral amyloid angiopathy
  • Down syndrome
  • Mass spectrometry
  • Neuropathology

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