What is the dominant aβ species in human brain tissue? A review

Gillian C. Gregory, Glenda M. Halliday

Interest in the beta amyloid (Abeta) peptides continues to grow due to their known accumulation in the brains of patients with Alzheimer's disease and recent tantalising evidence that reducing such accumulations can reverse disease-associated functional deficits. Abeta peptides are naturally produced in every cell by proteolytic cleavage of the amyloid precursor protein with two main alloforms (40 or 42 amino acids) both of which are disease associated. The identification that genetic mutations causing Alzheimer's disease impact on Abeta production and clearance have allowed for the manipulation of these pathways in cellular and animal models. These studies show that the amount and type of Abeta in the brain has significant consequences on neural function. However, there have been significant difficulties in the conversion of these findings into successful treatments in humans. In this review we concentrate on data from human studies to determine any comparative differences in Abeta production and clearance that may assist with better treatment design and delivery. Abeta40 is the dominant peptide species in human cerebrospinal fluid accounting for approximately 90% of total Abeta under normal conditions. However, similar studies using disease free human brain tissue do not correlate with these findings. In these studies, concentrations of Abeta40 are low with Abeta42 often identified as the dominant species. The data suggest preferential brain tissue utilisation and/or clearance of Abeta40 compared with Abeta42, findings which may have been predicted by their physiochemical differences. In Alzheimer's disease this equilibrium is disrupted significantly increasing Abeta peptide levels in brain tissue. The disease-specific increase in Abeta40 brain tissue levels in Alzheimer's disease appears to be an important though overlooked pathological change compared with the well-documented Abeta42 change observed both in the aged and in Alzheimer's disease. These findings are discussed in association with Abeta peptide function and a model of toxicity developed.