Impact of Tau on Neurovascular Pathology in Alzheimer's Disease.

Elisa Canepa,Silvia Fossati

doi:10.3389/fneur.2020.573324

Abstract

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.

Highlights

Alzheimer’s Disease, Neurovascular Unit and Blood-Brain Barrier DysfunctionAlzheimer’s disease (AD) is a progressive and deadly neurodegenerative disorder recognized by the World Health Organization as the most prevalent form of dementia [1]
Besides the documented effects of Aβ deposition around cerebral blood vessels (BVs), recent evidence indicates that tau pathology induces cerebral vascular dysfunction (CVD) [21,22,23], and that the presence of hippocampal perivascular tau strictly correlates with blood brain barrier (BBB) permeability and loss of integrity [24], prompting new questions to elucidate the molecular mechanisms through which tau toxicity affects the cerebral vasculature, in both AD and other tauopathies
To better dissect how tau pathology may affect cerebrovascular function, we propose below some of the molecular and cellular mechanisms which have been shown to be affected by tau, and may mediate its effects on the vessel walls

Summary

Introduction

Alzheimer’s Disease, Neurovascular Unit and Blood-Brain Barrier DysfunctionAlzheimer’s disease (AD) is a progressive and deadly neurodegenerative disorder recognized by the World Health Organization as the most prevalent form of dementia [1]. Transmigration of blood-borne cells, such as PB-MoM, has been reported in cerebral areas with increased ICAM-1 expression, associated with neurofibrillary pathology, in Tg SHR72 rat model which stably expresses human tau protein truncated at amino acids 151–391 (aa 151-391/4R) [142], confirming the role of tau in triggering detrimental changes in BBB.

Results

Conclusion