Dunn, J. F. | bioRxiv Science

bioRxiv2020

Deregulation of brain endothelial CD2AP in Alzheimer's disease impairs Reelin-mediated neurovascular coupling

Genetic variations in CD2-associated protein (CD2AP) predispose to Alzheimers disease (AD) but the underlying mechanisms remain unknown. Here, we show that a cerebrovascular loss of CD2AP is associated with cognitive decline in AD and that genetic downregulation of CD2AP in brain endothelial cells impairs memory function in two distinct mouse models. Mice with reduced CD2AP in brain microvessels display decreased resting cerebral blood flow, impaired functional hyperemia and vasomotion. In brain endothelial cells, CD2AP regulates the levels and signaling of ApoE receptor 2 elicited by Reelin glycoprotein. Activation of the CD2AP-ApoER2 pathway with Reelin mitigates the toxic effects of A{beta} on resting blood flow and vasomotion of brain vessels depleted of CD2AP. Thus, we demonstrate that deregulation of CD2AP perturbs specific functions and segments of the cerebral microvasculature and propose that targeting CD2AP molecular partners may offer refined therapeutic strategies for the treatment of AD.

neuroscience↗

bioRxiv2018

Novel use of Diffusion Tensor Imaging to Delineate the Rat Basolateral Amygdala

The amygdaloid complex, including the basolateral nucleus (BLA) contributes crucially to emotional and cognitive brain functions, and is thus a major target of research in both humans and rodents. However, delineating structural amygdala plasticity in both normal and disease-related contexts using neuroimaging has been hampered by the difficulty of unequivocally identifying the boundaries of the BLA. This challenge is a result of poor contrast between BLA and the surrounding gray matter, including other amygdala nuclei. Here we describe a novel DTI approach to enhance contrast, enabling optimal identification of BLA in rodent brain from MR images. We employed this methodology together with a slice-shifting approach to measure BLA volume. We then validated the results by direct comparison to both histological and cellular-identity (parvalbumin)-based conventional techniques for defining BLA in the same brains used for MRI. We also confirmed the BLA region using DTI based tractography. The novel approach used here enables accurate and reliable delineation of BLA. Because this nucleus is involved in, and is changed by, developmental, degenerative and adaptive processes, the instruments provided here should be highly useful to a broad range of neuroimaging studies. Finally, the principles used here are readily applicable to numerous brain regions and across species.\n\nSummary StatementUse of MRI directionally encoded diffusion tensor imaging (DTI) can delineate the basolateral amygdala (BLA) and volumes derived from DTI were found to match those obtained using histological methods. Our approach can be used to identify the BLA.

neuroscience↗