Vascular amyloid accumulation alters the gabaergic synapse and induces hyperactivity in a model of cerebral amyloid angiopathy

Pablo Cisternas, Xavier Taylor, Abigail Perkins, Orlando Maldonado, Elysabeth Allman, Ricardo Cordova, Yamil Marambio, Braulio Munoz, Taylor Pennington, Shunian Xiang, Jie Zhang, Ruben Vidal, Brady Atwood, Cristian A. Lasagna-Reeves

Research output: Contribution to journalArticlepeer-review

Abstract

Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of β-amyloid (Aβ), other amyloids are known to associate with the vasculature. Alzheimer's disease (AD) is characterized by parenchymal Aβ deposition and intracellular accumulation of tau as neurofibrillary tangles (NFTs), affecting synapses directly, leading to behavioral and physical impairment. CAA increases with age and is present in 70%–97% of individuals with AD. Studies have overwhelmingly focused on the connection between parenchymal amyloid accumulation and synaptotoxicity; thus, the contribution of vascular amyloid is mostly understudied. Here, synaptic alterations induced by vascular amyloid accumulation and their behavioral consequences were characterized using a mouse model of Familial Danish dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature. The mouse model (Tg-FDD) displays a hyperactive phenotype that potentially arises from impairment in the GABAergic synapses, as determined by electrophysiological analysis. We demonstrated that the disruption of GABAergic synapse organization causes this impairment and provided evidence that GABAergic synapses are impaired in patients with CAA pathology. Understanding the mechanism that CAA contributes to synaptic dysfunction in AD-related dementias is of critical importance for developing future therapeutic interventions.

Original languageEnglish (US)
Article numbere13233
JournalAging Cell
Volume19
Issue number10
DOIs
StatePublished - Oct 1 2020

Keywords

  • GABAergic synapses
  • cerebral amyloid angiopathy
  • synaptotoxicity
  • vascular amyloid

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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