Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

Abstract

Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species.

Lymphocytes Protect Cortical Neurons Against Excitotoxicity Mediated by Kainic Acid, an in vitro Model for Neurodegeneration

“…Indeed, in the archetypal autoimmune CNS disease, multiple sclerosis, it is established that lymphocytes invade the CNS and contribute to the neuropathology and a role for neuroinflammation has been implicated in numerous CNS diseases including Alzheimer's disease and Parkinson's disease. [10][11][12] However, studies also suggest that lymphocytes may have a neuroprotective role in the CNS when investigated using models of spinal cord injury, facial nerve axotomy and ischaemia.13-16 Our findings are in agreement with a previous study which focused specifically on the consequence of exposing organotypic cultures to the specific T cell subtypes.17 It revealed that both Th1 and Th2 cells were protective in a contact independent manner and the activation of these cell types led to increased neuroprotection. However in contrast to our study, this protection was against secondary damage initiated by explantation of tissue from living animal to the culture dish whereas our own study utilised established models of neurodegeneration.…”

“…Indeed, in the archetypal autoimmune CNS disease, multiple sclerosis, it is established that lymphocytes invade the CNS and contribute to the neuropathology and a role for neuroinflammation has been implicated in numerous CNS diseases including Alzheimer's disease and Parkinson's disease. [10][11][12] However, studies also suggest that lymphocytes may have a neuroprotective role in the CNS when investigated using models of spinal cord injury, facial nerve axotomy and ischaemia. [13][14][15][16] Our findings are in agreement with a previous study which focused specifically on the consequence of exposing organotypic cultures to the specific T cell subtypes.…”

‘O’ blood type is associated with larger grey-matter volumes in the cerebellum

“…Although no concrete evidence has yet been found in support of an association between ABO blood type, neural development, and neural protection, a recent histological study found that in 'A' blood type the expression of the ABO antigens is modulated at the level of the brain vascular endothelium (Wang et al, 2013). Since endothelial dysfunction is molecularly associated with neurodegeneration of the Alzheimer's type (Grammas et al, 2011;Lyros et al, 2014), it is possible that ABO-dependent modulation of endothelial function might contribute as a risk factor for (or protection factor against) accumulation of Alzheimer's pathology. Although this is only a speculation, a major mechanism by which the 'H' antigen precursor might be implicated in a systemic protection against the vascular events which contribute to the initiation of the neurodegenerative cascade of Alzheimer's disease might be a positive influence exerted by an "H antigen endothelium" on the neighbouring tunica media and tunica adventitia, where cerebral beta-amyloid angiopathy is observed (Thal et al, 2008).…”

Blood-Brain Barrier Disruption Is an Early Event That May Persist for Many Years After Traumatic Brain Injury in Humans

“…In particular, imaging (25) and animal modelling (23,26) studies in AD suggest BBB dysfunction is an early event in the course of disease and may contribute to its pathogenesis, perhaps as a result of impaired amyloid-² clearance or associated neuroinflammation (23,(27)(28)(29)(30)(31). Furthermore, neuropathology studies report complex vascular changes associated with BBB dysfunction in AD (32)(33)(34), with evidence of a correlation between histological evidence of BBB leakage and Alzheimer-type pathologies in 'normal' ageing (35).…”