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

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-beta (A beta) 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 A beta 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 A beta pool. Although the relationship between A beta and the appearance of cognitive symptoms is uncertain, available data support a strong relationship between the toxicity of A beta for neurons and the total A beta burden, including the soluble and fibrillar A beta, the A beta(42)/A beta(40) ratio, and A beta-proteoglycan reactivity. Proteoglycans have been shown to foster the formation of neurotoxic fibrillar A beta(42) 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.