Cerebral amyloid angiopathy, as the name might suggest, is an amyloidosis. It involves the build up of amyloid-β, and in some cases significant amounts of other forms of amyloid, in blood vessel walls in the brain, and dysfunction results. As the brain is a nutrient-hungry organ, any disruption of the blood supply will cause issues over the long term, contributing to the development of dementia. As most readers here no doubt know, amyloid-β deposits are the primary feature of early Alzheimer's disease, at the stages leading into mild cognitive impairment. Amyloid deposition and the changes in cellular biochemistry that result form the foundation for the later aggregation of hyperphosphorylated tau protein into neurofibrillary tangles, and it is tau and its surrounding harmful biochemistry that causes cell death and major neurological dysfunction. So perhaps it isn't too surprising to find that in cerebral amyloid angiopathy, it is also tau that is doing the real damage.
Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. Currently, there is no clear understanding of the mechanisms underlying the contribution of CAA to neurodegeneration. Despite the fact that CAA is highly associated with accumulation of Aβ, other types of amyloids have been shown to associate with the vasculature. Interestingly, in many cases, vascular amyloidosis is accompanied by significant tau pathology. However, the contribution of tau to neurodegeneration associated to CAA remains to be determined.
We used a mouse model of Familial Danish Dementia (FDD), a neurodegenerative disease characterized by the accumulation of Danish amyloid (ADan) in the vasculature, to characterize the contribution of tau to neurodegeneration associated to CAA. We performed histological and biochemical assays to establish tau modifications associated with CAA in conjunction with cell-based and electrophysiological assays to determine the role of tau in the synaptic dysfunction associated with ADan. We demonstrated that ADan aggregates induced hyperphosphorylation and misfolding of tau.
Moreover, in a mouse model for CAA, we observed tau oligomers closely associated to astrocytes in the vicinity of vascular amyloid deposits. We finally determined that the absence of tau prevents synaptic dysfunction induced by ADan oligomers. In addition to demonstrating the effect of ADan amyloid on tau misfolding, our results provide compelling evidence of the role of tau in neurodegeneration associated with ADan-CAA and suggest that decreasing tau levels could be a feasible approach for the treatment of CAA.