Abstract
The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer’s disease (AD) and related neurodegenerative diseases is increasingly recognized, however, the underlying mechanisms remain obscure. There is growing evidence that in addition to Aβ deposition, accumulation of hyperphosphorylated oligomeric tau contributes significantly to AD etiology. Tau oligomers are toxic and it has been suggested that they propagate in a “prion-like” fashion, inducing endogenous tau misfolding in cells. Their role in VCID, however, is not yet understood. The present study was designed to determine the severity of vascular deposition of oligomeric tau in the brain in patients with AD and related tauopathies, including dementia with Lewy bodies (DLB) and progressive supranuclear palsy (PSP). Further, we examined a potential link between vascular deposition of fibrillar Aβ and that of tau oligomers in the Tg2576 mouse model. We found that tau oligomers accumulate in cerebral microvasculature of human patients with AD and PSP, in association with vascular endothelial and smooth muscle cells. Cerebrovascular deposition of tau oligomers was also found in DLB patients. We also show that tau oligomers accumulate in cerebral microvasculature of Tg2576 mice, partially in association with cerebrovascular Aβ deposits. Thus, our findings add to the growing evidence for multifaceted microvascular involvement in the pathogenesis of AD and other neurodegenerative diseases. Accumulation of tau oligomers may represent a potential novel mechanism by which functional and structural integrity of the cerebral microvessels is compromised.
Highlights
The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer’s disease (AD) and related neurodegenerative diseases is increasingly recognized, the underlying mechanisms remain obscure
Because we showed that oligomeric tau accumulates in cerebrovascular endothelial and smooth muscle cells in various tauopathies including AD, we sought to determine whether vascular Aβ and oligomeric tau may coexist in the cerebrovasculature
The major finding of the present study is that tau oligomers accumulate in cerebral microvasculature of human patients with AD and progressive supranuclear palsy (PSP), in association with vascular endothelial and smooth muscle cells
Summary
The importance of vascular contributions to cognitive impairment and dementia (VCID) associated with Alzheimer’s disease (AD) and related neurodegenerative diseases is increasingly recognized, the underlying mechanisms remain obscure. There is growing evidence that a spectrum of vascular and microvascular pathologies (including neurovascular uncoupling, endothelial dysfunction, blood brain barrier disruption, cerebral microhemorrhages etc) contribute to initiation and/or progression of neurodegenerative diseases, including Alzheimer’s disease (AD) [1,2,3,4] To recognize this paradigm, shift the phrase “vascular contributions to cognitive impairment and dementia. In addition to AD, tau oligomers have been identified in other tauopathies including progressive supranuclear palsy (PSP) [23], Parkinson’s disease (PD), dementia with Lewy bodies (DLB) [24] and in subjects with Huntington’s disease (HD) [25] suggesting a common pathogenic role Despite these advances, the role of oligomeric tau in cerebromicrovascular abnormalities associated with neurodegenerative diseases remains obscure. We examined a potential link between CAA and vascular deposition of tau oligomers in the Tg2576 mouse model
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