The neglected co-star in the dementia drama: the putative roles of astrocytes in the pathogeneses of major neurocognitive disorders

Abstract

Alzheimer's disease (AD) and vascular dementia are the major causes of cognitive disorders worldwide. They are characterized by cognitive impairments along with neuropsychiatric symptoms, and that their pathogeneses show overlapping multifactorial mechanisms. Although AD has long been considered the most common cause of dementia, individuals afflicted with AD commonly exhibit cerebral vascular abnormalities. The concept of mixed dementia has emerged to more clearly identify patients with neurodegenerative phenomena exhibiting both AD and cerebral vascular pathologies-vascular damage along with β-amyloid (Aβ)-associated neurotoxicity and τ-hyperphosphorylation. Cognitive impairment has long been commonly explained through a 'neuro-centric' perspective, but emerging evidence has shed light over the important roles that neurovascular unit dysfunction could have in neuronal death. Moreover, accumulating data have been demonstrating astrocytes being the essential cell type in maintaining proper central nervous system functioning. In relation to dementia, the roles of astrocytes in Aβ deposition and clearance are unclear. This article emphasizes the multiple events triggered by ischemia and the cytotoxicity exerted by Aβ either alone or in association with endothelin-1 and receptor for advanced glycation end products, thereby leading to neurodegeneration in an 'astroglio-centric' perspective.