Alzheimer’s disease (AD), the most common cause of dementia, is a fast-growing epidemic that represents an enormous human, social and economic burden in our society. Despite extensive efforts to develop new therapies, all the clinical trials performed to date have been ineffective.This highlights the relevance of identifying the molecular mechanisms that drive the disease from its earliest stages, where potential intervention and disease-modifying strategies might be more efficient.
AD is characterized by two neuropathological hallmarks: amyloid plaques, consisting of extracellular deposits of amyloid beta, the cleavage product of APP (amyloid precursor protein) and intracellular accumulations of tau protein (neurofibrillary tangles, NFT). The appearance of NFT correlates with neurodegeneration and with the cognitive impairments associated with the disease progression. Interestingly, these pathogenic protein forms start to appear in specific neuronal subpopulations following a very conserved regional pattern. The most vulnerable neurons in AD are the excitatory neurons of the entorhinal cortex layer II (ECII), where NFT are present even before the first symptoms appear. The reason why these alterations appear earlier in these specific cells is unknown and represents one of the major challenges in the AD field. Understanding the mechanisms responsible for the early degeneration of these cells in AD would help to find new therapeutic targets to intervene at the earliest AD stages, potentially preventing further damage and helping to prevent or delay the disease progression. Therefore, the main objective of this project is to identify mechanisms and/or pathways associated with the vulnerability of ECII neurons to NFT formation in AD.
