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Understanding selective neuronal vulnerability in Alzheimer’s disease

Periodic Reporting for period 2 - NEVULA (Understanding selective neuronal vulnerability in Alzheimer’s disease)

Période du rapport: 2020-09-01 au 2021-08-31

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.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.
To identify mechanisms behind selective neuronal vulnerability to AD we used a systems biology approach that uses the specific biology of ECII neurons to highlight disease-associated genes. From this study we selected 4 different gene targets that might be central for the selective vulnerability of ECII neurons to AD. We modulated these genes in EC neurons both in vivo and in vitro and determined how they affect neuronal biology and whether they lead to AD-related pathological alterations. Our results showed that down-regulation of one of these genes, with previous unknown function in neurons, leads Tau protein accumulation, microglia activation and ECII neuron loss.

Cell-type specific data from AD patients has only been available for the past few years due to methodological limitations. However, until now, these studies are either focused on a different brain region or at advanced stages of the disease. We have generated cell-specific transcriptomics data from the entorhinal cortex of 5 control and 5 preclinical AD patients (with amyloid and tau pathology in the entorhinal but no clinical symptoms of AD). These data will be essential to clarify the most initial pathological events in human AD.
This project has helped to validate our system-level approache as a valuable tool to identify new mechanisms and potential therapeutic targets for AD. We have also generated cell-specific data of the alterations that take place in the most vulnerable region to AD before the disease onset.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.
Mouse brain. Magenta: neurons where we changed the expression of a gene. Yellow: microglia cells.