Mechanisms linking cerebrovascular dysfunction and tauopathy: Adding a layer of epiregulatory complexity.

Intracellular accumulation of hyperphosphorylated misfolded tau proteins are found in many neurodegenerative tauopathies, including Alzheimer's disease (AD). Tau pathology can impact cerebrovascular physiology and function through multiple mechanisms. In vitro and in vivo studies have shown that alterations in the blood-brain barrier (BBB) integrity and function can result in synaptic abnormalities and neuronal damage. In the present review, we will summarize how tau proteostasis dysregulation contributes to vascular dysfunction and, conversely, we will examine the factors and pathways leading to tau pathological alterations triggered by cerebrovascular dysfunction. Finally, we will highlight the role epigenetic and epitranscriptomic factors play in regulating the integrity of the cerebrovascular system and the progression of tauopathy including a few observartions on potential therapeutic interventions. LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc.