Molecular mechanisms underlying neurodegeneration in dementias: CD33 and TREM2.

Frontotemporal dementia (FTD) and Alzheimer's disease (AD) are two complex neurodegenerative disorders. Despite massive research and drug development, there are still no therapies that slow down or stop their progression. Several genes have been associated to both pathologies suggesting that a common molecular pathway could exist and is yet unknown. Mutations in genes related to neuroinflammation, including CD33 and TREM2, may be predisposing factors to these diseases. Two CD33 SNPs and one in TREM2 were described to be risk factors associated with Late Onset Alzheimer disease (LOAD). In particular, CD33 SNPs rs3856444 and rs12459419 major alleles give elevated risk of LOAD and they directly modulate CD33 exon 2 splicing efficiency. Moreover, the rare heterozygous missense variant rs75932628-T in TREM2 showed a strong association and could impair TREM2 ability to activate microglial cells. In order to assess the presence of these polymorphisms in our cohort we analyzed 216 Caucasians with LOAD and 50 healthy controls. We used High Resolution Melting analysis (HRM) on genomic DNA from whole blood of the patients and we sequenced by Sanger method individuals showing different melting curves and we used these as reference in our analysis. Our patients showed the coinheritance of rs12459419 and rs3865444 SNPs. Moreover, we identified a third SNP in CD33 exon 2 rs2455069 which belongs to a LD SNPs block previously identified, associated to a greater cognitive decline. We found that all patients analyzed for SNP rs75932628 in TREM2 gene are homozygous for the wild-type allele. However, some individuals are heterozygous for a close SNP rs143332484 that could associated to AD in our population. Further investigations are in progress to understand the mechanism of action of these two genes.