Biology subjects

Strickland, S.

Publications and source records attributed to Strickland, S..

2 recordsLinked to original sources

bioRxiv2017

Neutrophil adhesion in brain capillaries contributes to cortical blood flow decreases and impaired memory function in a mouse model of Alzheimer’s disease

The existence of cerebral blood flow (CBF) reductions in Alzheimers disease (AD) patients and related mouse models has been known for decades, but the underlying mechanisms and the resulting impacts on cognitive function and AD pathogenesis remain poorly understood. In the APP/PS1 mouse model of AD we found that an increased number of cortical capillaries had stalled blood flow as compared to wildtype animals, largely due to leukocytes that adhered in capillary segments and blocked blood flow. These capillary stalls were an early feature of disease development, appearing before amyloid deposits. Administration of antibodies against the neutrophil marker Ly6G reduced the number of stalled capillaries, leading to an immediate increase in CBF and to rapidly improved performance in spatial and working memory tasks. Our work has thus identified a cellular mechanism that explains the majority of the CBF reduction seen in a mouse model of AD and has also demonstrated that improving CBF rapidly improved short-term memory function. Restoring cerebral perfusion by preventing the leukocyte adhesion that plugs capillaries may provide a novel strategy for improving cognition in AD patients.

neuroscience↗

bioRxiv2017

Knockdown of Liver-Derived C1 Inhibitor Results in Brain Pathology in mice

Plasma proteins and activated immune cells are known contributors of vascular brain disorders. However, the mechanisms and routes involved are still unclear. In order to understand the cross-talk between plasma proteins and the brain, we knocked down circulating C1 inhibitor (C1INH) in wild-type (WT) mice using antisense-oligonucleotide (ASO) technique and examined the brain. C1INH is a plasma protein inhibitor of vascular inflammation induced by activation of the kallikrein-kinin system (KKS) and the complement system. This knockdown induced the activation of the KKS but spared the activation of the classical complement system. Activation of the KKS induced an upregulation of the bradykinin pathway in the periphery and the brain, resulting in hypotension. Blood-brain barrier (BBB) permeability, plasma protein extravasations, activated glial cells and elevated levels of IL-1beta, IL-6, TNF-alpha, and iNOS were detected in brains of C1INH ASO treated mice. Infiltrating innate immune cells were evident, entering the brain through the lateral ventricle walls and the neurovascular units. The mice showed normal motor functions, however, cognition was impaired. Altogether, our results highlight the important role of regulated plasma-C1INH as a gatekeeper of the neurovascular system. Thus, manipulation of C1INH in neurovascular disorders might be therapeutically beneficial.

neuroscience↗