Physiological roles for amyloid beta peptides

Abstract

Alzheimer's disease is recognized post mortem by the presence of extracellular senile plaques, made primarily of aggregation of amyloid beta peptide (Abeta). This peptide has consequently been regarded as the principal toxic factor in the neurodegeneration of Alzheimer's disease. As such, intense research effort has been directed at determining its source, activity and fate, primarily with a view to preventing its formation or its biological activity, or promoting its degradation. Clearly, much progress has been made concerning its formation by proteolytic processing of the amyloid precursor protein, and its degradation by enzymes such as neprilysin and insulin degrading enzyme. The activities of Abeta, however, are numerous and yet to be fully elucidated. What is currently emerging from such studies is a diffuse but steadily growing body of data that suggests Abeta has important physiological functions and, further, that it should only be regarded as toxic when its production and degradation are imbalanced. Here, we review these data and suggest that physiological levels of Abeta have important physiological roles, and may even be crucial for neuronal cell survival. Thus, the view of Abeta being a purely toxic peptide requires re-evaluation.

Figure 1. Cartoon depicting the proteolytic processing of amyloid precursor protein (APP) via non-amyloidogenic (left) and amyloidogenic (right) cleavage

Non-amyloidogenic cleavage occurs when α-secretase acts to liberate sAPPα and C83, the latter being cleaved by γ-secretase to generate p3. Amyloidogenic cleavage by β-secretase liberates sAPPβ and the residual peptide is cleaved to produce C88 and Aβ. Aβ in turn can be degraded by enzymes including neprilysin, insulin degrading enzyme and endothelin cleaving enzyme (not shown).

Figure 2. Synthesis, trafficking and retrieval of Ca²⁺ channels from the plasma membrane

Cartoon depicting the synthesis, trafficking and retrieval of Ca²⁺ channels from the plasma membrane under normoxia (upper picture). During sustained hypoxia, a rise of ROS from mitochondria triggers increased Aβ formation which has multiple effects (see text for full description) including direct neuroprotection, increased transcription of protective factors such as vascular endothelial growth factor (VEGF) via stabilization of HIF, and altered trafficking of Ca²⁺ channels so that more are present and active in the plasma membrane.