Amyloid-β as a Key Player in Cerebrovascular Dysfunction in Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent cause of dementia in the elderly. AD neuropathology is mainly characterized by the accumulation of intracellular aggregates of the protein tau and extracellular accumulation of the amyloid-β (Aβ) peptide, in the form of soluble oligomers and insoluble plaques. Cerebrovascular disorder (CVD) is a further hallmark of AD and causes decreased blood flow and perfusion, deterioration of the blood–brain barrier (BBB), and loss of the microvasculature (Zlokovic, 2011). Risk factors for AD and CVD substantially overlap and include diabetes and hypertension. The two-hit hypothesis for AD suggests that damage to the brain vessels (hit one) can lead to BBB dysfunction, hypoperfusion, decreased availability of energy substrates, and increased production and reduced clearance of Aβ—leading to Aβ accumulation in the brain (hit two), thereby rendering the brain milieu vulnerable to neuronal dysfunction and neurodegeneration (Zlokovic, 2011). In line with this hypothesis, changes in cerebral blood flow and local hypoxia/ischemia have been observed in early AD patients and in patients with mild cognitive impairment (MCI), who are at high risk for AD (Zlokovic, 2011). Moreover, hypoxia signaling increases the transcription and activity of β-secretase and γ-secretase, the two enzymes involved in Aβ production (reviewed in Salminen et al., 2017).

Notably, both Aβ and tau have been related to morphological and functional changes in the vasculature of AD patients and mouse models of AD. Aβ deposits within cerebral small vessels lead to cerebral amyloid angiopathy (CAA), a vascular feature of AD. Conversely, CAA may aggravate hypoxia and impair clearance of protein aggregates, further accelerating AD pathology (Zlokovic, 2011; Salminen et al., 2017). Aged mice overexpressing tau P301L (Tg4510), a tau variant associated with frontotemporal dementia, show abnormal blood vessel morphology, including reduced …

Correspondence should be addressed to Gustavo T. Stelzer at gustavo.stelzer{at}bioqmed.ufrj.br or Ricardo A. S. Lima-Filho at rfilho{at}bioqmed.ufrj.br.