Analysis of β-Amyloid Peptide Degradation In Vitro

The accumulation of insoluble Aβ peptide aggregates in the brain is the diagnostic feature of Alzheimer's disease. Identical deposits are seen in the elderly who are at risk for this disease. The formation of the approx 4 kDa Aβ peptide is implicated as a key component in the development of Alzheimer's disease pathology. Genetic evidence strongly supports this contention (1,2), as well as a number of demonstrated relevant biological activities of the Aβ peptide such as its neurotoxicity (3) and proinflammatory properties (4). A great deal of attention has been focused on the processes involved in the generation of Aβ peptide. In contrast, the fate of this peptide once it has been released from the cell is less well understood. Recently, this situation has been changing as studies on the clearance of Aβ peptide are being published. The identification of Aβ-degrading enzymes produced in the brain, their class, and selectivity, as well as their cellular origin, are important unresolved questions. One key issue of Aβ peptide clearance is whether the brain may be limited in its capacity to degrade this protein, as all cells produce Aβ, yet it is seen to accumulate only in brain tissue. Because alterations in Aβ peptide clearance may potentially contribute to increased levels and to the development of insoluble Aβ deposits in the brains of afflicted individuals, this chapter focuses on specific approaches to clarifying Aβ peptide-clearance mechanisms.