Vascular amyloidosis impairs the gliovascular unit in a mouse model of Alzheimer’s disease

Abstract

Reduced cerebral blood flow impairs cognitive function and ultimately causes irreparable damage to brain tissue. The gliovascular unit, composed of neural and vascular cells, assures sufficient blood supply to active brain regions. Astrocytes, vascular smooth muscle cells, and pericytes are important players within the gliovascular unit modulating vessel diameters. While the importance of the gliovascular unit and the signals involved in regulating local blood flow to match neuronal activity is now well recognized, surprisingly little is known about this interface in disease. Alzheimer's disease is associated with reduced cerebral blood flow. Here, we studied how the gliovascular unit is affected in a mouse model of Alzheimer's disease, using a combination of ex vivo and in vivo imaging approaches. We specifically labelled vascular amyloid in living mice using the dye methoxy-XO4. We elicited vessel responses ex vivo using either pharmacological stimuli or cell-specific calcium uncaging in vascular smooth muscle cells or astrocytes. Multi-photon in vivo imaging through a cranial window allowed us to complement our ex vivo data in the presence of blood flow after label-free optical activation of vascular smooth muscle cells in the intact brain. We found that vascular amyloid deposits separated astrocyte end-feet from the endothelial vessel wall. High-resolution 3D images demonstrated that vascular amyloid developed in ring-like structures around the vessel circumference, essentially forming a rigid cast. Where vascular amyloid was present, stimulation of astrocytes or vascular smooth muscle cells via ex vivo Ca(2+) uncaging or in vivo optical activation produced only poor vascular responses. Strikingly, vessel segments that were unaffected by vascular amyloid responded to the same extent as vessels from age-matched control animals. We conclude that while astrocytes can still release vasoactive substances, vascular amyloid deposits render blood vessels rigid and reduce the dynamic range of affected vessel segments. These results demonstrate a mechanism that could account in part for the reduction in cerebral blood flow in patients with Alzheimer's disease.media-1vid110.1093/brain/awv327_video_abstractawv327_video_abstract.

Lymphatics in Neurological Disorders: A Neuro-Lympho-Vascular Component of Multiple Sclerosis and Alzheimer’s Disease?

“…The progressive accumulation of Aβ in the brain vasculature, however, often culminates in cerebral amyloid angiopathy (CAA), a pathological feature that correlates well with the extent of cognitive impairment in AD (Greenberg et al, 2004; Thal et al, 2008). Amyloid deposits, in the form of ring-like structures wrapped around the brain’s blood vessels in a way that prevents contact between the astrocytic endfeet and the endothelial cell wall, compromises the functioning of both the astrocytes and the vascular smooth-muscle cells and impairs the cerebral blood flow (Kimbrough et al, 2015). Therefore, the high prevalence of CAA in AD patients evidently results from the combination of a decreased efflux and an increased influx of Aβ peptides across the BBB (Zlokovic, 2004).…”

“…Failure of the paravascular ISF bulk-flow pathways, together with the consequent progressive damage to the BBB, are reportedly associated with the increased degree of CAA observed in AD patients and animal models (Hawkes et al, 2014; Kimbrough et al, 2015; Weller et al, 2008). Aging, the main risk factor for sporadic AD, affects the functioning of paravascular ISF bulk-flow mechanisms and leads to CAA, mainly owing to age-related morphological changes in the vessels and specifically to arterial degeneration (Hawkes et al, 2011, 2013; Kress et al, 2014).…”

“…Moreover, Apo-Eε4, the major genetic risk factor for sporadic AD, can also affect not only the integrity of the neurovasculature but also the paravascular drainage of Aβ (Bell et al, 2012; Chakrabarty et al, 2015), both probably associated with the deleterious effects of Apo-Eε4 on pericyte and glial function (Bell et al, 2012; Chakrabarty et al, 2015). Nevertheless, it is now widely accepted that the proper functioning of smooth muscle cells, pericytes and astrocytes is of great importance for the maintenance of ISF perivascular drainage, and particularly for the removal of Aβ through the glymphatic pathway (Iliff et al, 2012; Kimbrough et al, 2015). Astrocytic expression of aquaporin 4 (AQP4) is essential for the proper flow of CSF through the interstitium and the most striking effects on the glymphatic pathway were obtained by the modulation of AQP4 levels (Iliff et al, 2012); following intracerebral injection the clearance of interstitial Aβ 1–40 through the glymphatic pathway was reduced by ≈55% in Aqp4-null mice relative to wild-type controls.…”

A role for ion channels in perivascular glioma invasion

“…Therefore, it is not surprising that several neurological disorders including temporal lobe epilepsy, stroke, and Alzheimer’s disease have been reported to be associated with disturbances of the gliovascular unit (Seifert et al 2006; Kimbrough et al 2015). Malignant gliomas also exhibit focal breaches in the BBB and dysfunctions in gliovascular coupling (Wolburg et al 2003, 2012; Watkins et al 2014).…”

Retinal changes in the Tg-SwDI mouse model of Alzheimer’s disease

“…In mammalian retinas, astrocytes are present solely in the vascular regions (Schnitzer, 1988) and mostly in the retinal NFL (Ramírez et al, 1996). Image J software was used for semi-automated cell counts and gliosis assessment (Kimbrough et al, 2015). Statistical significance (p<0.05) was assessed using two-tailed independent t-tests.…”