The Neurovascular Unit Dysfunction in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disease worldwide. Histopathologically, AD presents with two hallmarks: neurofibrillary tangles (NFTs), and aggregates of amyloid β peptide (Aβ) both in the brain parenchyma as neuritic plaques, and around blood vessels as cerebral amyloid angiopathy (CAA). According to the vascular hypothesis of AD, vascular risk factors can result in dysregulation of the neurovascular unit (NVU) and hypoxia. Hypoxia may reduce Aβ clearance from the brain and increase its production, leading to both parenchymal and vascular accumulation of Aβ. An increase in Aβ amplifies neuronal dysfunction, NFT formation, and accelerates neurodegeneration, resulting in dementia. In recent decades, therapeutic approaches have attempted to decrease the levels of abnormal Aβ or tau levels in the AD brain. However, several of these approaches have either been associated with an inappropriate immune response triggering inflammation, or have failed to improve cognition. Here, we review the pathogenesis and potential therapeutic targets associated with dysfunction of the NVU in AD.

Relationship Between Amyloid-β Deposition and Blood–Brain Barrier Dysfunction in Alzheimer’s Disease

“…This process may lead to the production and activation of a variety of toxic molecules that ultimately affect the function of BBB ( Moore et al, 2002 ). Specifically, the interaction of Aβ with a variety of receptors, including CR3 (Mac-1) fAβ and Aβ/SRA, will trigger increased expression of NF-κB, and secretion of ROS, TNF-α, complement components and other pro-inflammatory substances ( Yang et al, 2011 ; Zhang et al, 2011 ; Soto-Rojas et al, 2021b ). In the transgenic AD mouse model, it was observed that the accumulation of Aβ caused NF-κB upregulation with, the destruction of BBB integrity, and a decline in mouse learning ability ( Scheffer et al, 2021 ).…”

Brain-Derived Exosomal Proteins as Effective Biomarkers for Alzheimer’s Disease: A Systematic Review and Meta-Analysis

“…The two core neuropathological hallmarks of AD are Aβ and tau protein aggregates. The first hallmark is the presence of Aβ deposits in the brain parenchyma as neuritic plaques and around cerebral blood vessels as cerebral amyloid angiopathy [51][52][53]. The Aβ peptide present in amyloid plaques is approximately 36-43 amino acids in length, and is generated from APP by a series of proteolytic cleavages followed by a broad range of posttranslational modifications [54].…”

“…Aβ plays a major role in neurotoxicity and neural function; therefore, accumulation of dense plaques in the hippocampus, amygdala, and cerebral cortex can cause stimulation of astrocytes and microglia, damage to the axons and dendrites, loss of synapses, and cognitive impairments [55][56][57][58]. The second hallmark is neurofibrillary tangles (NFTs) and hyperphosphorylated tau, which accumulate intracellularly and are typically accompanied by neuronal loss [51]. The tau protein is hyperphosphorylated in AD, which leads to compromised microtubules, thereby disrupting several cellular processes, such as proliferation, differentiation, protein trafficking, and cellular morphology [59,60].…”

Role of Neuron and Glia in Alzheimer’s Disease and Associated Vascular Dysfunction

“…The BBB, comprised of microvessels and endothelial cells (in the brain capillaries) along with pericytes, astrocytic end-feet, microglia, and neuronal processes of NVU, restricts the undesired exchange of toxic materials between the CNS and systemic blood circulation. A dysfunctional NVU and BBB may precede AD pathology, involving extracellular Aβ-associated reactive astroglia and microglia, vascular wall thickening, reduction in smooth muscle cells, and neuritic loss (Soto-Rojas et al, 2021 ). The subsequent induction of astrocyte and microglia-induced inflammatory mediators, such as IL-1, TNFα, and the complement component subunit 1q (C1q; Liddelow et al, 2017 ), further enhance NVU and BBB damage through a feedback loop, with the accelerated generation of p-tau and NFT.…”

“…The subsequent induction of astrocyte and microglia-induced inflammatory mediators, such as IL-1, TNFα, and the complement component subunit 1q (C1q; Liddelow et al, 2017 ), further enhance NVU and BBB damage through a feedback loop, with the accelerated generation of p-tau and NFT. The NVU-linked microglial cells associate with Aβ via CR1 (CD35) fAβ receptors, which appears as a critical reason for altered BBB and NVU integrity (Fonseca et al, 2016 ; Soto-Rojas et al, 2021 ). Microglial participation through increased contact size at the basement membrane is a key to the development of perivascular glia limitans surrounding the brain capillary vessels of the NVU, particularly during inflammation.…”