Alzheimer’s Disease: Physiological and Pathogenetic Role of the Amyloid Precursor Protein (APP), its Aβ-Amyloid Domain and Free Aβ-Amyloid Peptide

  • K. Beyreuther
  • C. L. Masters
Part of the Research and Perspectives in Alzheimer’s Disease book series (ALZHEIMER)

Summary

To understand synaptic loss and neurodegeneration in Alzheimer’s disease, we have tried to consider the physiological functions of the amyloid precursor protein (APP), its Aβ-amyloid domain and of free Aβ peptide. The latter is a normal metabolic product of APP and the principal subunit of the amyloid plaques that are characteristic of Alzheimer’s disease. From studies in transgenic Drosophila melanogaster and primary mammalian neurons, we suggest that, in neurons, APP exhibits as a physiological function the negative regulation of synaptic strength whereas in nonneuronal cells APP appears to regulate cell-cell and cell-matrix adhesion.

Since the axonal transport of APP is dependent on the Aβ domain, this finding suggests that the Aβ sequence could function as an axonal sorting signal of APP. It also indicates that the Aβ region could bind to molecules that control the recruitment of APP into axonally transported vesicles.

In neurons, metabolism of APP releasing the Aβ peptide was found to occur at all sorting stations, such as at the ER/cisGolgi and TGN/endosomes producing intracellular Aβ peptide as well as at the cell surface leading to secretory Aβ peptide. Regarding the Aβ species generated in the different neuronal compartments, the long form of Aβ (Aβ42) is produced in the ER/cisGolgi and at or near the cell surface, and short Aβ (Aβ40) is produced in the TGN/endosomal compartment and also at or near the cell surface.

Given an Aβ function as an axonal sorting signal of APP, release of Aβ may regulate the axonal transport of APP. Not only does the removal of the Aβ sequence from APP abolish axonal APP transport, but also free Aβ could — by blocking the APP binding site of the axonal transport machinery of APP — serve such a regulatory, physiological function. Excess intracellular and extracellular Aβ may convert the latter physiological function of Aβ to a pathogenic one by inhibiting the axonal transport of those proteins that use the same transport system as APP.

Because the apoEε4 allele may be associated with higher cholesterol levels in neurons, and because higher risk of developing Alzheimer’s disease and axonal transport of membrane proteins are cholesterol dependent, we studied the influence of cholesterol on neuronal Aβ generation. By lowering the cholesterol level in neuronal cultures with statins (HMG-CoA reductase inhibitors), the formation of secretory and intracellular Aβ is drastically reduced. Since the amount of Aβ produced by neurons is cholesterol dependent, both the physiological and pathogenic regulation of APP transport by Aβ appears to be controled in neurons by cholesterol. This finding implies a link between brain cholesterol. APP transport, Aβ production and the risk of developing Alzheimer’s disease. These intriguing relationships open new strategies to influence the progression of Alzheimer’s disease by modulating cholesterol biosynthesis of neurons with statins.

Keywords

Dementia Influenza Beach Neurol Fibril 

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© Springer-Verlag Berlin Heidelberg 2001

Authors and Affiliations

  • K. Beyreuther
  • C. L. Masters

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