Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Abstract

Deposition of amyloid-β (Aβ) in cerebral arteries, known as cerebral amyloid angiopathy (CAA), occurs both in the setting of Alzheimer's disease and independent of it, and can cause cerebrovascular insufficiency and cognitive deficits. The mechanisms leading to CAA have not been established, and no therapeutic targets have been identified. We investigated the role of CD36, an innate immunity receptor involved in Aβ trafficking, in the neurovascular dysfunction, cognitive deficits, and amyloid accumulation that occurs in mice expressing the Swedish mutation of the amyloid precursor protein (Tg2576). We found that Tg2576 mice lacking CD36 have a selective reduction in Aβ1-40 and CAA. This reduced vascular amyloid deposition was associated with preservation of the Aβ vascular clearance receptor LRP-1, and protection from the deleterious effects of Aβ on cerebral arterioles. These beneficial vascular effects were reflected by marked improvements in neurovascular regulation and cognitive performance. Our data suggest that CD36 promotes vascular amyloid deposition and the resulting cerebrovascular damage, leading to neurovascular dysfunction and cognitive deficits. These findings identify a previously unrecognized role of CD36 in the mechanisms of vascular amyloid deposition, and suggest that this scavenger receptor is a putative therapeutic target for CAA and related conditions. T here is increasing evidence that alterations in the structure and function of cerebral blood vessels contribute to the brain dysfunction underlying Alzheimer's disease (AD) (1, 2). Whereas resting cerebral blood flow (CBF) is reduced early in course of AD (3, 4), the increase in CBF induced by brain activity (functional hyperemia), a vital mechanism matching the metabolic demands of active neurons with the delivery of nutrients through blood flow, is suppressed (5, 6). With disease progression, deposition of amyloid-β (Aβ) in cerebral blood vessels, a condition known as cerebral amyloid angiopathy (CAA), damages cerebrovascular cells, weakens vessel walls, and disrupts vascular function further (7). CAA also occurs independent of AD and has emerged as a frequent cause of brain hemorrhage, silent infarct, and cognitive impairment (8, 9).Studies in mice overexpressing mutated forms of the amyloid precursor protein (APP) have demonstrated that Aβ peptides, especially Aβ1-40, which accumulates preferentially in cerebral blood vessels, alter cerebrovascular function, resulting in vasoconstriction, impaired functional hyperemia, and inability of the endothelium to regulate vascular tone (10-12).These studies have raised the possibility that Aβ, in addition to damaging neurons and glia, also threatens the cerebral blood supply and increases the brain's susceptibility to hypoxia-ischemia (1, 13). Furthermore, considering that vascular transport is a key pathway for clearance of Aβ from the brain (14), these vascular alterations also may enhance the accumulation of Aβ in brain and cerebral blood vessels.Converging evidence indicates that Aβ exerts i...

Pericytes of the neurovascular unit: key functions and signaling pathways

“…Pericytes degenerate in AD, as shown by post-mortem brain tissue studies in humans 50,69–71 and animal models of AD 26,72,73 . Moreover, plasma PDGF-BB levels are increased in AD patients 74 and soluble PDGFRβ (sPDGFRβ) levels, reflecting pericyte injury 75 , are increased in cerebrospinal fluid (CSF) of subjects with mild dementia and transgenic AD and pericyte-deficient murine models 73 , suggesting dysfunction in PDGF-BB/PDGFRβ pathway compared to control subjects and in experimental models.…”

Accelerated pericyte degeneration and blood–brain barrier breakdown in apolipoprotein E4 carriers with Alzheimer’s disease

“…8,12,29,31 The PDGFR coverage of brain capillaries was determined as PDGFR -positive area (percentage) occupying lectin-positive endothelial capillary profiles, as we and others have previously described. 8,8,29,31,33 Pericyte numbers were determined by counting the number of PDGFR -positive cell bodies on the abluminal side of the endothelial membrane (lectin) that colocalized with DAPI (4 0 ,6-diamidino-2-phenylindole)-positive nuclei using the ImageJ Cell Counter plug-in, as we and others previously described. 6,[31][32][33] The number of pericytes was expressed per mm 2 of tissue.…”

Vascular and Metabolic Factors in Alzheimer’s Disease and Related Dementias: Introduction

“…Importantly, these vascular abnormalities are observed in the absence of deposition of Aβ in amyloid plaques or around cerebral blood vessels (cerebral amyloid angiopathy), suggesting that soluble or oligomeric Aβ is the vasotoxic species. The cerebrovascular effects of Aβ are mediated in large part by activation of the free radical-producing enzyme NADPH oxidase through the innate immunity receptor CD36, and are reversible by pharmacological or genetic approaches to scavenge radicals or block their production (Han et al, 2015; Iadecola et al, 1999; Nicolakakis et al, 2008; Park et al, 2013; 2008). However, these neurovascular alterations become irreversible in advanced disease, due to accumulation of Aβ in cerebral blood vessels which leads to damage to endothelium, smooth muscle cells and pericytes (Park et al, 2013; 2014).…”

“…The cerebrovascular effects of Aβ are mediated in large part by activation of the free radical-producing enzyme NADPH oxidase through the innate immunity receptor CD36, and are reversible by pharmacological or genetic approaches to scavenge radicals or block their production (Han et al, 2015; Iadecola et al, 1999; Nicolakakis et al, 2008; Park et al, 2013; 2008). However, these neurovascular alterations become irreversible in advanced disease, due to accumulation of Aβ in cerebral blood vessels which leads to damage to endothelium, smooth muscle cells and pericytes (Park et al, 2013; 2014). Collectively, the evidence to date suggests that Aβ, in addition to its well-established effects on synaptic function, also targets cerebral blood vessels leading to neurovascular dysfunction and lowering the threshold for cerebral ischemic injury.…”

“…A paravascular pathway involving astrocytic end-feet (glymphatic system), which has the potential to clear Aβ from the brain (Iliff et al, 2012), has been recently discovered and could play a role. Cerebrovascular damage prevents Aβ removal and leads to amyloid accumulation in brain and vessels (Faraco et al, 2015; Park et al, 2013). Therefore, the health of the cerebral vasculature is critical for Aβ clearance, and vascular damage is likely to promote amyloid deposition also in AD.…”