David R. Drew

SignificanceAlzheimer’s disease does not occur in isolation, and there are many comorbidities associated with the disease, especially diseases of the vasculature. Atherosclerosis is a known risk factor for the subsequent development of Alzheimer’s disease; therefore, understanding how both diseases interact will provide a greater understanding of co-morbid disease progression and aid the development of potential new treatments.AimWe characterize hemodynamic responses and cognitive performance in APP/PS1 Alzheimer’s mice, atherosclerosis mice, and a mixed disease group (APP/PS1 and atherosclerosis) between the ages of 9 and 12 months.ApproachWhisker-evoked hemodynamic responses and recognition memory were assessed in awake mice, immunohistochemistry to assess amyloid pathology, and histology to characterize atherosclerotic plaque load.ResultsWe observed hemodynamic deficits in atherosclerosis mice (versus Alzheimer’s, mixed disease, or wild-type mice), with reduced short-duration stimulus-evoked hemodynamic responses occurring when there was no concurrent locomotion during the stimulation period. Mixed Alzheimer’s and atherosclerosis models did not show differences in amyloid beta coverage in the cortex or hippocampus or atherosclerotic plaque burden in the aortic arch vs relevant Alzheimer’s or atherosclerosis controls. Consistent with the subtle vascular deficits and no pathology differences, we also observed no difference in performance on the object recognition task across groups.ConclusionsThese results emphasize the importance of experimental design for characterizing vascular function across disease groups, as locomotion and stimulus duration impacted the ability to detect differences between groups. Although atherosclerosis did reduce hemodynamic responses, these were recovered in the presence of co-occurring Alzheimer’s disease, which may provide targets for future studies to explore the potentially contrasting vasodilatory mechanisms these diseases impact.

Functional and structural age-associated changes in the blood-brain barrier (BBB) may affect the neurovascular unit and contribute to the onset and progression of age-associated neurodegenerative pathologies, including Alzheimer’s disease. The current study interrogated the RNA profile of the BBB in an ageing human autopsy brain cohort and an ageing mouse model using combined laser capture microdissection and expression profiling. Only 12 overlapping genes were altered in the same direction in the BBB of both ageing human and mouse cohorts. These included genes with roles in regulating vascular tone, tight junction protein expression and cell adhesion, all processes prone to dysregulation with advancing age. Integrated mRNA and miRNA network and pathway enrichment analysis of the datasets identified 15 overlapping miRNAs that showed altered expression. In addition to targeting genes related to DNA binding and/or autophagy, many of the miRNAs identified play a role in age-relevant processes, including BBB dysfunction and regulating the neuroinflammatory response. Future studies have the potential to develop targeted therapeutic approaches against these candidates to prevent vascular dysfunction in the ageing brain.