Cerebral perfusion and glucose metabolism profiling reveal special phenotypes in the hAPOE3, hAPOE4, Trem2 risk, and doubled risks mice. (20th December 2022)

• Record Type: Journal Article
• Authors: Lin, Peter Bor‐Chian; Persohn, Scott C; Bedwell, Amanda A; Jiang, Lei; Eldridge, Kierra; Speedy, Rachael; Kotredes, Kevin P; Pandey, Ravi S; Williams, Harriet M; Oblak, Adrian L; Sasner, Michael; Howell, Gareth R; Carter, Gregory W; Lamb, Bruce T; Territo, Paul R
• Is Part Of: Alzheimer's & dementia. Volume 18(2022)Supplement 3
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-12-20
• Subjects: Alzheimer's disease -- Periodicals; Alzheimer Disease -- Periodicals; Dementia -- Periodicals; Démence; Maladie d'Alzheimer; Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 616.83
• DOI: 10.1002/alz.063682
• Languages: English
• ISSNs: 1552-5260

Abstract

Abstract: Background: Alzheimer's disease (AD) is the most common cause of dementia in the United States. Approximately 95% of patients have sporadic Late‐Onset AD (LOAD) which lacks an inheritance pattern. Therefore, identifying phenotypic patterns is critical for understanding disease progression. Among all the genetic markers which being identified as AD risks, and APOE4 confers the strongest one. The GWAS analysis also revealed a LOAD‐associated locus on the gene of TREM2. As the microglial receptor of APOE, the R47H variant on TREM2 increases the AD risk. In this study, how these risk alleles affect the brain phenotypes were assessed by MODEL‐AD. Method: We established an analytical scheme which elucidates the cerebral perfusion and metabolism profiles across 27 brain regions by using 64 Cu‐PTSM and 18 F‐FDG PET imaging platform in the mice with wild‐type, humanized APOE3 (hAPO ε3/ ε3 ), humanized APOE4 (hAPO ε4/ ε4 ), TREM2 risk (Trem2 R47H/R47H ), and doubled risks (hAPO ε4/ ε4 :Trem2 R47H/R47H ) alleles. Also, RNA‐seq results from the hemisphere samples were used to conduct the correlation between PET measurements and the gene expression changes from each animal cohort. Result: Longitudinal analysis (4mo animals as reference) revealed aging effects in each cohort. The male hAPOE4 mice and both sexes of Trem2 risk animals had hypo‐perfusion and metabolism, while female hAPOE4 mice showed an uncoupled hyper‐perfusion and hypo‐metabolism phenotype. In the doubled risks mice, perfusion and metabolism showed a mixed regional‐dependent phenotype. Cross‐sectional analysis (wildtype mice as reference) showed the effects of humanized genes. A reduction in glucose metabolism was discovered. Intriguingly, male risks mice also showed reduced in perfusion, while the female mice showed a metabolic uncoupling profile. Cross‐sectional analysis (hAPOE3 mice as reference) showed the effects of risk alleles. An overall reduction in both perfusion and metabolism was discovered in all animal cohorts. To confirm these findings, RNAseq showed the genes involved in cerebral perfusion, glucose transportation, and metabolism regulation were altered, which are consistent with the findings. Conclusion: These data suggest that the new perfusion‐metabolism strategy may help to identify AD‐related patterns. Moreover, they replicate clinical manifestations of subjects with the same variants. Finally, additional studies are needed to elucidate the mechanisms and etiology of this uncoupling phenomenon.