Blood‐brain barrier neuropathology in individuals with Down syndrome and Alzheimer’s disease

Abstract

AbstractBackgroundIndividuals with Down syndrome (DS) are the largest population at genetic risk of developing early‐onset Alzheimer’s disease (AD). Throughout their lifespan, individuals with DS develop the spectrum of AD neuropathology. By 40 years of age, mature amyloid beta plaques and tau neurofibrillary tangles are present in DS brains, followed by the development of AD dementia. Despite having a low frequency of vascular risk factors (i.e., hypertension, atherosclerosis), individuals with DS display significant cerebrovascular pathology, including cerebral amyloid angiopathy, increased white matter hyperintensities, microbleeds, microinfarcts, and enlarged perivascular spaces. Such pathological changes suggest that the blood‐brain barrier (BBB) undergoes neuropathological alterations and may be associated with the development of AD pathology, in DS. Nevertheless, BBB integrity has not been studied in DS. Our main objective is to investigate BBB pathology in the brains of people with DS and AD (DSAD).MethodPost‐mortem brain tissue was obtained from the ABC‐DS study, NIH Neurobiobank, and BrightFocus Foundation. BBB components (basement membrane, endothelial cells, pericyte cell number) and BBB leakage were assessed by free‐floating immunohistochemistry in human brain tissue sections from the occipital cortex of individuals with DSAD (49‐55 years old), and their age‐matched neurotypical controls (48‐57 years old). Brain sections were digitized, and BBB components and vessel morphology were quantified using ImageJ.ResultOur preliminary data suggest that, compared to age‐matched controls, adults with DSAD have a lower number of pericytes and lower Collagen‐IV load. A proportion of DSAD cases also had lower endothelial cell coverage and shorter blood vessels. Moreover, fibrinogen leakage was observed in the brain parenchyma of DSAD brains. Interestingly, some individuals with DSAD displayed no BBB pathological changes.ConclusionIndividuals with DS have pathological alterations in the BBB. However, some people with DSAD may be resilient to such changes. Studies are ongoing to determine if BBB changes in DS are associated with the development and progression of AD neuropathology.