Amyloid Precursor Protein Neurotrophic Properties As a Target to Cure Alzheimer's Disease

Amyloid Precursor Protein Neurotrophic Properties As a Target to Cure Alzheimer's Disease

Delacourte Andre
Published: European Neurological Disease 2006
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Alzheimer's disease (AD) is a frequent brain pathology of the elderly, with a far more complicated aetiology than what was thought in the 1990s. The complexity particularly comes from the co-existence of two degenerating processes, tau aggregation and amyloid beta (Aß) deposition, that affect polymodal association brain areas, a feature never observed in non-human primates and difficult to model.1 Genetic studies have shown that Aß precursor protein (PP) plays a central role in familial autosomic dominant AD.2 Familial AD (FAD) and sporadic AD (SAD) have the same neuropathological phenotype, with Aß accumulation in the gray matter of the neocortex.3 Thus, there is a huge body of evidence that Aß is the neurotoxic that causes both FAD and SAD.4 The question is whether it is that simple. The National Institute for Health and Medical Research (Inserm) Research Center 815 have noted that the basic mechanisms are different in FAD and SAD, as there is a clear overproduction of Aß species in FAD as well as a modification of the ratio of Aß of 42 to 40.5 This is not observed in SAD and it is assumed that the aetiology could be linked to a fibrillogenesis or clearance dysfunction of APP metabolites.


Furthermore, in most studies, the role of tau has been understated for a long time. To apprehend this role, the Inserm team has developed a spatio-temporal analysis of tauopathy in many brain areas of hundreds of nondemented and demented patients. This prospective multidisciplinary study showed that tauopathy always progresses in the brain along a precise and invariable pathway, from the entorhinal then hippocampal formation to polymodal association areas and ending in primary regions and many subcortical areas. The cognitive impairment follows the progression of the affected brain regions.6 In strict parallelism, neocortical Aß deposits increase in quantity and heterogeneity, suggesting a direct link between both neurodegenerative processes.1 Deciphering this link is the key to finding a relevant therapeutic strategy.

SAD–A Tauopathy Fuelled by APP Dysfunction

The parallelism and synergy between tau and Aß aggregation led the Inserm team to search for an APP molecular event linking the two degenerating processes. APP is a ubiquitous protein found in all cell types of all species, suggesting a basic and important role that remains to be identified. A neurotrophic activity for APP and secreted APP (sAPP) is often mentioned.7 Therefore, a loss of function of APP rather than a gain of toxic function of Aß could also be a reasonable hypothesis to explain the stimulation of tauopathy and neurodegeneration.

Complementary to this study of Aß species, the Inserm team found no obvious modification of APP holoprotein in correlation with the pathology. However, carboxy-terminal fragments of APP (APPCTFs) were found to be significantly diminished during the course of AD and well correlated with the progression of tauopathy.8 Beta, alpha and gamma stubs were also significantly decreased in the brain tissue of individuals having an inherited form of AD linked to mutations of presenilin 1, showing a general defect common to FAD and SAD. An important role of the gamma stubs (also named APP intracellular domain (AICD)) as gene regulators could explain their involvement in the disease, as these fragments are dramatically reduced in AD.9–11 These observations led to other therapeutic strategies focused on the concept of a loss of function of APP-stimulating tauopathy, in good agreement with other teams.12–14 Thus, restoring the neuroprotection properties of APP could be a therapeutic strategy to slow down or cure AD.

The ‘Four-hit’ Hypothesis

In the literature, the key events of APP metabolism are generally summarised as follows:

  • The neurotoxic Aß is produced following an N-terminal cleavage by beta-site APP-cleaving enzyme (BACE)1, an aspartic protease that releases a beta stub (see Figure 1).15 This beta stub is then cleaved by a γ-secretase activity to release Aß and a cytosolic fragment named AICD.16 This is the amyloidogenic, or ‘the evil’, pathway.

  • In parallel, an APP cleavage takes place inside the Aß region through an a-secretase activity (possibly a disintegrin and metalloproteinase domain 10 (ADAM 10) or ADAM 17) releasing an alpha stub. The latter is cleaved by the γ-secretase activity to release p3 and AICD.17–19 This is the nonamyloidogenic, or ‘the good’, pathway, as there is no production of the neurotoxic Aß but a release of metabolites with neurotrophic properties – sAPPa and AICD.


Stimulating the non-amyloidogenic pathway at the expense of the amyloidogenic one seems the most promising avenue to prevent or treat AD.20

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