Diversity of Aβ deposits in the aged brain: A window on molecular heterogeneity?

The Aβ peptide forms a morphologically heterogeneous assortment of aggregates in the brains of patients with Alzheimer's disease. The reasons for the diversity of the histopathologically identified lesions (Aβ-plaques and cerebral β-amyloid angiopathy) are uncertain. However, there is growing evidence for the existence of higher order structural heterogeneity in protein molecules with the same amino acid sequence and differential involvement in disease. Focused analysis of plaque morphotypes could yield novel insights into the organization and function of putative protein variants in the diseased brain. In addition to classical amyloid-selective dyes, new techniques are emerging to undertake such analyses, including selective, small molecule binding agents, specific antibodies, and conformationally sensitive optical probes. By illuminating the relationships between specific lesions and their molecular components, these agents can help to clarify the complex pathology of Alzheimer's disease.