Abstract
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.
Highlights
Alzheimer disease (AD), the most common form of dementia, is characterized by the extracellular deposition of parenchymal and vascular β-amyloid (Aβ), intracellular accumulation of tau as neurofibrillary tangles (NFTs), neuronal cell loss, and significant inflammation [15, 39]
Previous efforts in AD and AD-related dementias have aimed to understand the connection between parenchymal amyloid, tau aggregation, and neurodegeneration, with the contribution of vascular amyloid pathology to tau aggregation and neurodegeneration remaining understudied
Using a set of in vitro and in vivo approaches, we proposed the existence of two possible mechanisms of how accumulation of Danish amyloid (ADan) vascular amyloid may trigger tau misfolding
Summary
Alzheimer disease (AD), the most common form of dementia, is characterized by the extracellular deposition of parenchymal and vascular β-amyloid (Aβ), intracellular accumulation of tau as neurofibrillary tangles (NFTs), neuronal cell loss, and significant inflammation [15, 39]. Different amyloid peptides are deposited in these conditions, the tau deposits are antigenically and biochemically indistinguishable [25, 27, 28, 34, 35]. These findings support a unifying pathological mechanism in which vascular accumulation of amyloidogenic peptides triggers a complex pathological cascade leading to tau accumulation and neurodegeneration
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