Amyloid-beta oligomers (AβO) have been proposed as the most potent neurotoxic and inflammation inducers in Alzheimer’s disease (AD). AβO contribute to AD pathogenesis by impairing the production of several cytokines and inflammation-related signaling pathways, such as the Janus kinases/signal transducer of transcription factor-3 (JAK/STAT3) pathway. STAT3 modulates glial activation, indirectly regulates Aβ deposition, and induces cognitive decline in AD transgenic models. However, in vivo studies using an AβO microinjection rat model have not yet explored STAT3 role. The main purpose of this study was to elucidate if a single microinjection of AβO could promote an increased expression of STAT3 in glial cells favoring neuroinflammation and neurodegeneration. We designed a model of intrahippocampal microinjection and assessed glial activation, cytokines production, STAT3 expression, and neurodegeneration in time. Our results showed robust expression of STAT3 in glial cells (mainly in astrocytes) and neurons, correlating with neuronal death in response to AβO administration. A STAT3 inhibition assay conducted in rat primary hippocampal cultures, suggested that the induction of the transcription factor by AβO in astrocytes leads them to an activation state that may favor neuronal death. Notwithstanding, pharmacological inhibition of the JAK2/STAT3 pathway should be focused on astrocytes because it is also essential in neurons survival. Overall, these findings strongly suggest the participation of STAT3 in the development of neurodegeneration.

The present study evaluated the risk effect of 12 Single Nucleotide Polymorphisms in the SORL1 gene in the Mexican population using Late-Onset Alzheimer’s Disease (LOAD) and control subjects. Considering APOE as the strongest genetic risk factor for LOAD, we conducted interaction analyses between single nucleotide polymorphisms (SNPs) and the APOE genotype. Methods: Patients were interviewed during their scheduled visits at neurologic and geriatric clinics from different institutions. The LOAD diagnosis included neurological, geriatric, and psychiatric examinations, as well as the medical history and neuroimaging. Polymorphisms in SORL1 were genotyped by real-time PCR in 156 subjects with LOAD and 221 controls. APOE genotype was determined in each study subject. Allelic, genotypic, and haplotypic frequencies were analyzed; an ancestry analysis was also performed. Results: The A/A genotype in rs1784933 might be associated with an increased LOAD risk. Two blocks with high degree linkage disequilibrium (LD) were identified. The first block composed by the genetic variants rs668387, rs689021 and rs641120 showed a positive interaction (mainly the rs689021) with rs1784933 polymorphism. Moreover, we found a significant association between the APOE ε4 allele carriers and the variant rs2070045 located in the second LD block. Conclusion: The rs1784933 polymorphism is associated with LOAD in Mexican patients. In addition, the presence of APOE ε4 allele and SORL1 variants could represent a genetic interaction effect that favors LOAD risk in the Mexican population. SNPs have been proposed as genetic markers associated with the development of LOAD that can support the clinical diagnosis. Future molecular studies could help understand sporadic Alzheimer’s Disease (AD) among the Mexican population, where currently there is a sub-estimate number in terms of disease frequency and incidence.