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Understanding selective neuronal vulnerability in Alzheimer’s disease

Periodic Reporting for period 1 - NEVULA (Understanding selective neuronal vulnerability in Alzheimer’s disease)

Reporting period: 2018-09-01 to 2020-08-31

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.

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.
During this reporting period we have modulated the levels of 4 different potential candidates responsible for the vulnerability of ECII neurons both in neurons cultured in a plate and also in different mouse models. We have studied their function by identifying the pathways that are affected when their levels are increased or decreased and the potential association of these pathways with AD pathology. We have also determined how these genes affect tau protein and if they lead to pathological alterations in tau. These experiments have helped us to selected one candidate among the initial 4 that seems to be more promising in terms of triggering changes compatible with AD pathology, and we are currently studying the molecular mechanisms involved. We have also obtained control and preclinical brain samples from human donors that we are using to characterise the alterations that happen in the most vulnerable region in AD and at its earliest stages.
Cell-type specific data from AD patients has only been available for the past 2 years. However, until now, these studies are either focused on a different region or, if they are from the entorhinal cortex, they are obtained from advanced cases of the disease. The human data that we will obtain with this project will be essential to understand the most initial pathological events in AD. By comparing if some of the pathways are common to the ones that we have identified with the bioinformatics analysis and the experiments in mice, we will be able to identify the molecular events that initiate the disease in the most vulnerable region to AD. In the future, we expect that these data will lead to the development of therapies to target AD at its earliest stages, before damage and neuronal loss is further extended. We believe that these potential therapies will be more efficient in delaying or stopping the disease progression.
Mouse brain. Magenta: neurons where we changed the expression of a gene. Cyan: nuclei.