APOEe4*TREM2 and sickle cell trait in a late onset Alzheimer’s disease mouse model

Abstract

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease associated with neuroinflammation, dysregulated neurovascular coupling, abnormal neuroplasticity, and neuropathological makers, including tau and β‐amyloid deposition. Advancing age is the greatest risk factor, and apolipoprotein E (APOE) e4 and triggering receptor expressed on myeloid cells 2 (TREM2) are genetic risk factors for late‐onset AD, which comprises >95% of all AD cases. Sickle cell trait (SCT) refers to the heterozygous inheritance of the sickle cell hemoglobin mutation. Studies from our laboratory and others show that SCT is associated with increased risk of microvascular complications and peripheral inflammation. Given the role of cerebral small vessel disease and inflammation in the pathogenesis of AD, we hypothesized that SCT may interact with late‐onset AD gene variants, resulting in earlier development of cognitive impairments, possibly via promoting neuroinflammation.MethodTo test our hypothesis, 10‐12 weeks old mice carrying APOE e4*TREM2 combined late‐onset AD genes were transplanted with bone marrow from humanized Townes mice with SCT (AS) or normal (AA) hemoglobin, following irradiation. Using a longitudinal cross‐sectional design, 3 cohorts were evaluated at 8, 12, and 18 months for presence of cognitive deficits using rodent behavioral testing. Mice were sacrificed immediately following behavioral testing, and brain tissue was evaluated using immunohistochemistry and Golgi‐Cox impregnation histology.ResultBehavioral testing suggested only age‐related cognitive impairments. There were no significant differences in neuroinflammation at any age between AS and AA mice in the hippocampus or corpus callosum and external capsule. Within genotypes, there was an age dependent increase in neuroinflammation, between 8 and 12 months in the hippocampus (p < 0.0001, p = 0.0002) and 12 versus 18 months in white matter tracts (p < 0.0001, p < 0.0001). There were no significant differences in the dendritic spine density or the proportion of immature spines between AS and AA mice. However, within genotypes there was significant differences between 12 and 18 months (p < 0.0001, p < 0.0001), with 18 months having lower spine density and higher proportion of immature spines.ConclusionAddition of SCT to a background of APOE e4*TREM2 did not result in earlier onset of cognitive impairment or more severe neuroinflammation.