A transcriptome analysis of TREM2 mutant patients: implications for the understanding on microglia dysfunction as a risk factor for Alzheimer´s disease

Abstract

Alzheimer´s disease (AD), the most prevalent form of late-onset dementia, is the sixth leading cause of death in the USA, placing a substantial burden on the health care system (Alzheimer´s association annual report). Only a small fraction of all AD cases (< 5%) are related to mutations in APP, PSEN1, and PSEN2 genes that lead to heritable early-onset AD. Most patients with late onset AD (LOAD) do not have the familial AD mutations. For these cases, multifactorial environmental factors, and different genetic factors are risk factors for developing LOAD. Variants in triggering receptor expressed on myeloid cells 2 (TREM2), which expression is restricted to microglia have now been associated with increased risk of developing LOAD. TREM2 is essential for maintaining microglia function during stress events, and its signaling was shown to be crucial for microglia to detect and respond to neurodegeneration cues. In this sense, addressing the molecular signature and functional elements of the genome of cells and tissues in TREM2 variants seems a good strategy to advance the research in the field and develop therapeutic strategies for the control of the AD. Thus, the aim of the present proposal is to perform single nucleus RNA-sequencing of brain samples from TREM2 mutant patients and age-matched controls. For this, the brains will be analyzed by single nucleus-sequencing (Nuc-Seq), a DNA barcoding technique for analysis of RNA profiles of single nuclei from frozen or lightly fixed tissues at high throughput. This proposal is part of a huge project in which we will compare a very large sample of brains that harbor the early onset Alzheimer gene mutation- PSEN1 to sporadic age-related disease mutations, such as TREM2. The analysis of this invaluable resource is essential for the better understanding of AD with an important impact to the research field. (AU)