Age-Related Changes in Brain Extracellular Space Affect Processing of Amyloid-β Peptides in Alzheimer's Disease

Abstract

Alzheimer's disease is a neurodegenerative disease in which aging is not only a major risk factor but a major determinant of onset, course, and pathogenesis. The synthesis of amyloid-β (Aβ) peptides by neurons and their excretion into the extracellular space (ECS) is a core feature of AD that begins more than two decades before the onset of clinical symptoms. The ECS resembles a syncytium with the appearance in electron micrographs of continuous channels and lakes separating the outer membranes of the neurons, neuroglia, and vascular elements embedded in it. It consists primarily of a proteoglycan matrix through which circulates an interstitial fluid, derived in part from cerebrospinal fluid (CSF). The process by which Aβ accumulates in the ECS includes decreased production of CSF, matrix proteoglycans, and ECS volume, all of which become more severe with advancing age and lead to an age-related increase in the Aβ pool. Although the relationship between Aβ and the appearance of cognitive symptoms is uncertain, available data support a strong relationship between the toxicity of Aβ for neurons and the total Aβ burden, including the soluble and fibrillar Aβ, the Aβ42/Aβ40 ratio, and Aβ-proteoglycan reactivity. Proteoglycans have been shown to foster the formation of neurotoxic fibrillar Aβ42 and neuritic plaques that enhance neuronal and synaptic damage and eventual loss culminating in the onset and progression of dementia. As this process depends upon age-related events, it suggests that the successful control of AD lies in finding effective means of prevention.