Exploring the function of stalled capillary flow as a novel mechanism for hypoperfusion in Alzheimer disease
Final Report Abstract
The circulatory system and the neurovascular unit are crucial components for the function and homeostasis of the brain. Although all neurological disorders have distinct pathological aspects – such as amyloid plaques found in Alzheimer’s disease (AD) – many share additional commonalities and recent evidence suggests that all neurodegenerative disorders such as AD, Parkinson, and dementia may share a common pathology: vascular dysfunction. Obstructed microcirculation due to a loss or alteration of vascular cells such as endothelium cells, leukocytes and pericytes, molecular changes within the vascular cells of the neurovascular unit, and/or inherited genes that may predispose individuals to cerebral vascular abnormalities may be subjacent causes of many neurological disorders. Classically, research focused on the neuronal aspect of those diseases, suggesting that the cause of AD is centered within the neuronal network of the brain. However, this view fails to consider that the essential cells of the neurovascular unit and the circulatory system are also involved during pathogenesis and may even be crucial at the initiation and progression of AD and other neurodegenerative diseases. It has been shown for many decades that patients and mouse models of AD display reduced cerebral blood flow (CBF). The reduced CBF in the cortex is caused by leucocytes, namely neutrophils, which can adhere to the endothelial cell wall and causeoccluded capillaries (stalls). Furthermore, we used non-linear imaging to measure the number of stalls in these capillaries and could show that these are elevated by about 5 times. During my past two years as a postdoctoral fellow in the Schaffer-Nishimura lab we demonstrated that an antibody against the neutrophil cell surface protein Ly6G is able to block neutrophil adhesion, consequently leading to neutrophil depletion. This results in increased CBF by 30% and releasing of capillary stalls by 75% within hours. Together with our collaborators at Weill Cornell we could obtain similar results using Arterial spin labeling MRI, a method to measure global perfusion of the brain. To elucidate if this novel mechanism has an influence on cognition, the mayor suffer of patients with AD, we performed a series of behavioral mouse experiments to measure episodic memory deficits, depression, and sensory-motor dysfunction. Using the antibody against Ly6G, cognitive functions recovered almost to wild-type levels whereas a control antibody did not show any improvement. Hence, we identified a novel cellular mechanism that has not been described before and that could explain the long-sought phenomenon of reduced brain blood flow in AD. This finding has great potential for new therapeutic targets in AD if stalling can be confirmed in AD patients.
Publications
- “Stalled Blood Flow in Brain Capillaries is Responsible for Reduced Cortical Perfusion in Mouse Models of Alzheimer’s Disease”. Nature medicine under revision
Cruz Hernandez JC, Bracko O, Kersbergen C, Muse V, Ivasyk I, Park L, Vinarcsik LK, Haft-Javaherian M, Cortes Canteli M, Kang Y, Zhou J, Beverly JD, Slack E, Otte G, Santisakultarm TP, Strickland S, Iadecola C, Nishimura N and Schaffer CB
(See online at https://doi.org/10.1016/j.jalz.2016.06.2186) - Lysosomal prosaposin trafficking impairment is a novel disease mechanism in frontotemporal lobar degeneration due to progranulin mutation. Nat Commun. 2017 May 25;8:15277
Zhou X, Sun L, Bracko O, Choi JW, Jia Y, Nana AL, Brady OA, Cruz Hernandez JC, Nishimura N, Seeley W, Hu F
(See online at https://doi.org/10.1038/ncomms15277) - Motor Rehabilitation Therapy after Stroke Improves performance in a different motor task: first translational evidence. Transl Stroke Res. 2017 Aug;8(4):347-350
El Amki M, Baumgartner P, Bracko O, Luft AR and Wegener S
(See online at https://doi.org/10.1007/s12975-016-0519-x) - (2018): Sensorimotor stroke alters hippocampo-thalamic network activity. In: Scientific reports 8 (1), S. 15770
Baumgartner P, El Amki M, Bracko O, Luft AR and Wegener S
(See online at https://doi.org/10.1038/s41598-018-34002-9)
