Neurogenesis: A New Key Player in the Progression of Alzheimer’s Disease and its Therapeutics.

Background: In mammals, adult neurogenesis occurs in two areas of thecentral nervous system (CNS): in the sub ventricular zone (SVZ) and in thesubgranularzone of the dentate gyrus (DG) of the hippocampus. The newlygenerated cells display neuronal morphology, generate action potentialsand receive functional synaptic inputs, their properties being therefore similarto those of mature neurones. Alzheimer’s disease (AD) is the widespreadcause of age-related dementia and is an age-related, progressiveand irreversible neurodegenerative disease that results in massive neuronaldeath and deterioration of cognitive functions. Methods: Here, we haveused male and female triple transgenic mice (3xTg-AD) harbouring threemutant genes (ß-amyloid precursor protein, presenilin-1 and tau) and theirrespective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and12 monthsof age to establish the link between AD and neurogenesis. Using immunohistochemistry,we determined the area density of proliferating cells withinthe SGZ of the DGand SVZ, measured by the presence of phosphorylatedHistone H3 (HH3), and their possible co-localisation with GFAP to excludea glial phenotype. Results: Both non-Tg and 3xTg-AD showed an age-dependentdecrease inneurogenesis. However, male 3xTg-AD mice demonstrateda further reduction in the production of new neurones from 9months of age (73% decrease) and a complete depletion at 12 months,when compared to controls. In addition, female3xTg-AD mice showed anearlier but equivalent decrease in neurogenesis at 4 months (reduction of63%) with an almost inexistent rate at 12 months (88% decrease) comparedto controls. This reduction in neurogenesis was directly associated with theincrease in the Lumber of ß-amyloid containing neurones in the hippocampus;which in the case of 3xgTg females was directly correlated. Less than2% of HH3 labelled cells displayed GFAP. Similar results were also replicatedin the SVZ. 3xTg-AD mice demonstrated a significant reduction incell proliferation from 3 months of age that was sustained through allages, compared to controls. Conclusions: Therefore, this generalisedimpairment of neurogenesis, may account for early changes in synapticplasticity and cognitive impairments that develop prior to gross neurodegenerativealterations in AD and could underlie the development of new rescuetherapies.P3-491 AGGRESSIVE