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Impact of Tau on Neurovascular Pathology in Alzheimer's Disease

Canepa, Elisa, Fossati, Silvia·2021·Frontiers in Neurology
DOI 10.3389/fneur.2020.573324PMC PMC7817626
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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.

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Figure 1 Molecular mechanisms underlying neurovascular tau toxicity in AD and other tauopathies. Neuronal transmission through (1) tunneling nanotubes (TNTs), (2) exosomes, (3) ectosomes, or (4) plasma membrane may account for extracellular tau, which can be internalized by neighboring neurons via (5) low-density lipoprotein receptor (LRP), (6) clathrin-mediated endocytosis, (7) micropinocytosis by heparin sulfate proteoglycans, or (1) TNTs. Tau is also detected in brain interstitial fluids, cerebrospinal fluid (CSF) and in blood, reflecting the intensity of neurodegeneration. Inside the neuron, hyperphosphorylated tau promotes microtubules disassembly, aggregates into oligomers and paired helical filaments (PHF) which, in turn, accumulate, leading to neurofibrillary tangles (NFT) deposition. Phosphorylated tau can interact with mitochondrial proteins, such as Drp1, triggering excessive mitochondrial fission and mitochondrial dysfunction, including elevated ROS production, Ca2+ homeostasis dysregulation, decreased ATP production, and ultimately caspase activation. Caspase-3 cleaved tau facilitates tau phosphorylation and self-aggregation, further exacerbating tau pathology. Tau can propagate to astrocytes and microglia, and be internalized via micropinocytosis and CX3CR1, respectively. In astrocytes, the accumulation of tau fibrils around the nucleus confers the characteristic tufted phenotype. Tau pathological species, through astrocytic end-feet and interstitial fluids, may spread to endothelial cells and pericytes, inducing blood brain barrier (BBB) disruption and permeability to blood-borne components, including peripheral blood monocyte-derived macrophages (PB-MoM), immunoglubulins (IgGs and IgMs), and α2-macroglobulin (α2M). Moreover, the presence of tau within glial cells induces the secretion of several pro-inflammatory cytokines and chemokines, such as IL-1β,−6, - 8,−10, IFNγ, and MCP-1, initiating a high inflammatory state, which contributes to BBB integrity loss.
Figure 1 Molecular mechanisms underlying neurovascular tau toxicity in AD and other tauopathies. Neuronal transmission through (1) tunneling nanotubes (TNTs), (2) exosomes, (3) ectosomes, or (4) plasma membrane may account for extracellular tau, which can be internalized by neighboring neurons via (5) low-density lipoprotein receptor (LRP), (6) clathrin-mediated endocytosis, (7) micropinocytosis by heparin sulfate proteoglycans, or (1) TNTs. Tau is also detected in brain interstitial fluids, cerebrospinal fluid (CSF) and in blood, reflecting the intensity of neurodegeneration. Inside the neuron, hyperphosphorylated tau promotes microtubules disassembly, aggregates into oligomers and paired helical filaments (PHF) which, in turn, accumulate, leading to neurofibrillary tangles (NFT) deposition. Phosphorylated tau can interact with mitochondrial proteins, such as Drp1, triggering excessive mitochondrial fission and mitochondrial dysfunction, including elevated ROS production, Ca2+ homeostasis dysregulation, decreased ATP production, and ultimately caspase activation. Caspase-3 cleaved tau facilitates tau phosphorylation and self-aggregation, further exacerbating tau pathology. Tau can propagate to astrocytes and microglia, and be internalized via micropinocytosis and CX3CR1, respectively. In astrocytes, the accumulation of tau fibrils around the nucleus confers the characteristic tufted phenotype. Tau pathological species, through astrocytic end-feet and interstitial fluids, may spread to endothelial cells and pericytes, inducing blood brain barrier (BBB) disruption and permeability to blood-borne components, including peripheral blood monocyte-derived macrophages (PB-MoM), immunoglubulins (IgGs and IgMs), and α2-macroglobulin (α2M). Moreover, the presence of tau within glial cells induces the secretion of several pro-inflammatory cytokines and chemokines, such as IL-1β,−6, - 8,−10, IFNγ, and MCP-1, initiating a high inflammatory state, which contributes to BBB integrity loss.CC BY · PubMed Central

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Metadata

Authors
Canepa, E., & Fossati, S.
Venue
Frontiers in Neurology
Publisher
Frontiers Media SA
Published
2021-01-07
Volume
11
ISSN
1664-2295
DOI
10.3389/fneur.2020.573324
PMC
PMC7817626
Cited by
67
References
58
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institutes of Health
  • Edward N. and Della L. Thome Memorial Foundation
  • Alzheimer's Association

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