Periodic Reporting for period 1 - NEVULA (Understanding selective neuronal vulnerability in Alzheimer’s disease)
Reporting period: 2018-09-01 to 2020-08-31
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 pyramidal neurons of the entorhinal cortex layer II (ECII), where NFT are present even before the first symptoms. 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 in the earliest AD stages, potentially preventing further damage in neuroanatomically connected regions and helping to prevent or delay the disease progression.
The main objective of the project is to identify mechanisms and/or pathways associated with the vulnerability of ECII neurons to NFT formation in AD. To do so we will test several potential targets that we have identified by bioinformatic analysis of cel-typel specific data. We will also generate cell-type specific data from postmortem brain samples obtained from donors with preclinical AD.