Amyloid in the ageing brain: New frameworks and perspectives.

Abstract

The amyloid cascade hypothesis has dominated research to understand the role of Aβ in AD but has never been fully accepted by the whole AD research community. Two alternative hypotheses, the presenilin hypothesis and the APP matrix approach, have been less intensively investigated. Relationships between AD-associated neuropathologies, ageing and dementia are complex in the older human population. Uncertainties and confounds in AD research suggest the theoretical frameworks that direct research require improvement. Here we present key concepts for the APP matrix approach including: i) dynamic balance between competing cleavages; ii) multiple disease associated drivers and pathways; iii) a systematic approach to describing and understanding all proteolytic fragments derived from APP and iv) full consideration of fundamental biochemical concepts such as dose-response relationships, competitive inhibition, competitive binding etc. for each proteolytic fragment. The APP matrix approach aims to: i) create a descriptive molecular map of all the proteolytic fragments generated by the APP proteolytic system; ii) characterise this map with reference to dynamic regulatory feedback loops and fundamental biochemical concepts; iii) describe and model differences in the behaviour of this system in different cell types and species and iv) generate a dynamic functional model to characterise how specific molecular and neuropathological features relating to the APP proteolytic system are associated with dementia.