The case for blood–brain barrier dysfunction in the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system β-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying β-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of β-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue.

Glial regulation of the blood-brain barrier in health and disease

“…The physical, molecular, and transporter barrier properties of the BBB are each responsible for maintaining CNS homeostasis [1,45,52]. Histopathological analysis of various neurologic diseases have revealed that BBB dysregulation and breakdown is a common feature in many of these disorders, lending proof to the hypothesis that a functional BBB is required for a healthy CNS [2,6,49,[53][54][55][56][57]. Moreover, there is evidence that this works in the opposite direction as well; that a healthy CNS microenvironment is essential for maintaining the functional barrier properties of the BBB via cross-talk between neural cells and ECs [2].…”

Emerging Concepts in Alzheimer's Disease

“…Though it was at one time suggested that AD/SDAT is a hippocampal dementia, the prevailing view is now that neocortical lesions are a necessary substrate of cognitive decline (158). Abnormalities of cerebral microcirculation (i.e., the neurovascular unit, which includes the capillary and arteriolar endothelium and surrounding pericytes, SMCs, and astrocytes) have been suggested as key elements in AD/SDAT pathogenesis (159)(160)(161). The role of the perivascular spaces (surrounding brain parenchymal vessels) in clearing brain parenchymal Aβ is discussed above, including with reference to the consequences of Aβ vaccination.…”

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

“…[3][4][5] Type 2 diabetes mellitus (T2DM) has been highlighted as a major risk factor for cognitive decline.…”

“…2 Such BBB impairment is mainly caused by hypoxia/ischemia and inflammation. [3][4][5] Type 2 diabetes mellitus (T2DM) has been highlighted as a major risk factor for cognitive decline. 6 However, the mechanisms involved are not completely understood.…”