A NEW MECHANISM FOR ALZHEIMER NEURODEGENERATION: FUNCTIONAL ANTAGONISM BETWEEN PRO-NGF, MATURE NGF AND THEIR RECEPTORS

The 95 % of Alzheimer’s patients is affected by the sporadic form, for which no cause or mechanism is known. Only symptomatic cures are presently available for Alzheimer’s Disease (AD). For the rare genetic forms, the responsible genes are known (the genes for the amyloid protein and the presenilins), but no clear mechanism has been to date identified for the sporadic form, and different mechanisms are postulated to lead to the neuropathological hallmarks of AD: amyloid plaques, neurofibrillary tangles of tau and cholinergic deficit. We have developed a mouse model (AD11 mice) that reporduces in a comprehensive and unique way the principal hallmarks of the disease. The study of AD11 mice has led us to discover a new molecular mechanism that leads in the brain of mice, to the development of Alzheimer’s neurodegeneration, namely an altered equilibrium of the activity of the Nerve Growth Factor (NGF), a neurotrophic factor for cholinergic neurons. The involvment of NGF in AD, in terms of a reduced activity, has been previously postulated, but it remained unclear whether and how the ensuing cholinergic deficit is connected to the amyloid and tau neuropathology, typical of AD. Our experimental results have allowed us to postulate that an increased activity of a “toxic” form of NGF, that constitutes the natural biosynthetic precursor of the “beneficial” form of NGF, might activate the biochemical cascade that leads to AD neuropathology. Recent clinical data in the literature support this hypothesis. The aim of this hypothesis-driven project is to test in a stringent way the actual validity of our framework hypothesis, that, if finally proven, would pave the way to the development of new therapeutical approaches to AD.