Abstract
Microangiopathy, including proliferation of small diameter capillaries, increasing vessel tortuosity, and increased capillary blockage by leukocytes, was previously observed in the aged rTg4510 mouse model. Similar gene expression changes related to angiogenesis were observed in both rTg4510 and Alzheimer’s disease (AD). It is uncertain if tau is directly responsible for these vascular changes by interacting directly with microvessels, and/or if it contributes indirectly via neurodegeneration and concurrent neuronal loss and inflammation. To better understand the nature of tau-related microangiopathy in human AD and in tau mice, we isolated capillaries and observed that bioactive soluble tau protein could be readily detected in association with vasculature. To examine whether this soluble tau is directly responsible for the microangiopathic changes, we made use of the tetracycline-repressible gene expression cassette in the rTg4510 mouse model and measured vascular pathology following tau reduction. These data suggest that reduction of tau is insufficient to alter established microvascular complications including morphological alterations, enhanced expression of inflammatory genes involved in leukocyte adherence, and blood brain barrier compromise. These data imply that 1) soluble bioactive tau surprisingly accumulates at the blood brain barrier in human brain and in mouse models, and 2) the morphological and molecular phenotype of microvascular disturbance does not resolve with reduction of whole brain soluble tau. Additional consideration of vascular-directed therapies and strategies that target tau in the vascular space may be required to restore normal function in neurodegenerative disease.
Highlights
Vascular dysfunction is increasingly recognized as a cooccurring pathological feature of neurodegenerative diseases including Alzheimer’s [3, 20]
Tau is closely associated with vasculature in humans and mice We hypothesized that tau may directly be contributing to the downstream vascular phenotype previously described in rTg4510 tau expressing mice [8]
Considering the increased proportion of capillaries without normal blood flow in rTg4510 mice, which we previously observed to be due to leukocyte adhesion to the endothelium [8], we investigated whether increased expression of cell adhesion molecules (CAMs) could be contributing to this phenotype
Summary
Vascular dysfunction is increasingly recognized as a cooccurring pathological feature of neurodegenerative diseases including Alzheimer’s [3, 20]. The Alzheimer’s Disease Neuroimaging Initiative identified that MRI measures of cerebral blood flow were among the first alterations in human subjects with mild cognitive impairment [36], and several other groups have confirmed disturbed blood flow with increasing clinical disease [15, 25, 48, 75]. Reductions in blood flow and other vascular pathologies evident by neuroimaging have been shown to be closely related to the neuropathological accumulation of tau protein [16, 40]. In tauopathies including Alzheimer’s disease and frontotemporal lobar dementia with MAPT mutations, regional changes in cerebral blood flow have been observed [10, 24, 64], implicating vascular dysfunction as a common feature of diseases that include tau accumulation. Pathological accumulation of Alzheimer’s disease proteins are known to have consequences
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