APP-Tau synergy

APP is a trans-membrane protein cleaved by different secretases, at the alpha, beta, beta’ and gamma sites (A). The cleavages release several APP carboxy-terminal fragments (APP-CTFs), that have likely a neurotrophic activity (B) and in parallel Abeta peptide (B’). A decrease of APP-CTFs is observed in Alzheimer’s disease, which is the potential enhancer of tau pathology and neurodegeneration (C). AD46 (C’) is also an early co-factor of tau pathology. The stimulated tau degenerating process will progress in brain areas, along cortico-cortical connections, from stages 1-3 (entorhinal and hippocampal formation) to stage 10 (all neocortical areas, via polymodal association areas (stage 7) (left part, D, E)).

Presented at the AD/PD congress in Sevilla, Spain, May 2003

ALZHEIMER'S DISEASE: A TRUE TAUOPATHY FUELED BY APP DYSFUNCTION

A. Delacourte

At the present time, the initiating cause of neurodegeneration in Alzheimer’s disease is still a matter of debate. A number of hypotheses are proposed including the extracellular neurotoxicity of Abeta, the intracellular one, or a loss of function of APP. However, the amyloid cascade hypothesis reflects the major trend of research: extracellular Abeta is the central cause, and could be neutralized by vaccination. In parallel, neurofibrillary degeneration, i.e tau pathology, has been described as a late and secondary event, in perfect disagreement with neuropathological observations (Fewster, Braak, Duyckaerts, Bierer, Hof, Mesulam, Price). Our biochemical spatiotemporal analysis of tau pathology in non-demented elderly patients from a prospective and multidisciplinary approach corroborates neuropathological findings. Indeed, tau pathology spreads progressively, invariably, hierarchically, from the transentorhinal cortex to the whole neocortex, along cortico-cortical connections. We have shown that tau pathology develops in parallel to Abeta deposition, and is even sometimes present before Abeta deposition. The fact that tau pathology is a neuron-to-neuron spreading phenomenon, and that the neocortical involvement is always found in the presence of Abeta deposits demonstrate that 1) AD is a real tauopathy 2) there is a synergy between amyloidosis and tauopathy 3) the early transformation and decrease of APP-carboxy terminal fragments (APP-CTFs), in parallel to tau pathology, is in favor of a loss of APP function as the central cause of AD. It could be explained by the loss of APP-CTFs trophic activities, provoking the extent of tau pathology. APP-CTFs are known to be modulating transcription factors.