Presenter of 1 Presentation
LEVERAGING GENETIC CONTEXT TO MODEL VASCULAR CONTRIBUTIONS TO COGNITIVE DECLINE AND DEMENTIA
Abstract
Aims
Vascular contributions to cognitive decline and dementia (VCID) are now widely appreciated but the underlying genetic causes remain elusive. Current studies relevant to VCID use mouse models focused on environmental risk factors such as diet-induced obesity. We have employed mouse genetic diversity to understand the mechanisms underlying VCID.
Methods
We performed a strain survey using amyloid drivers APPswe and PSEN1de9 (APP/PS1). APP/PS1 transgenes were backcrossed from C57BL/6J to nine strains including wild-derived WSB/EiJ, PWK/PhJ and CAST/EiJ. All strains were assessed for cerebral amyloid angiopathy (CAA). CAA is found in 85-95% of AD cases, and is one of the strongest vascular contributors to age-related cognitive decline.
Results
WSB showed the greatest propensity of CAA. Male and female WSB.APP/PS1 and WSB mice were aged from 4 to 18 months. Vascular amyloid was observed at 8 months in cortical and leptomeningeal vessels. These deposits colocalized with astrocyte processes, but were devoid of microglia and collagen. Brain transcriptional profiling identified genes relating to vascular health including basement membrane, endothelial function and blood vessel formation. Microbleeds were present in aged WSB mice – even in the absence of amyloid. Deficits in mitochondria function may underlie vascular dysfunction as high-resolution respirometry indicated a significant depression of respiration in the hippocampus from 4 months, prior to observed CAA. Efforts are underway to include clinically relevant genetic risk factors such as humanized amyloid, tau and apolipoprotein E.
Conclusions
These data suggest that the WSB genetic context provides a new platform to dissect vascular contributions to dementia and development of preclinical models.