Neprilysin Protects against Cerebral Amyloid Angiopathy and Aβ‐Induced Degeneration of Cerebrovascular Smooth Muscle Cells

Miners, Scott; Kehoe, Patrick Gavin; Love, Seth

doi:10.1111/j.1750-3639.2011.00486.x

Cited by 38 publications

(29 citation statements)

References 63 publications

(107 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…increased Aβ metabolism by the peptidase neprilysin could play a role (38), Aβ1-40 is rapidly removed from the brain by vascular transport and is less susceptible than Aβ1-42 to cleavage by neprilysin (39). Moreover, considering that Aβ1-40 is associated preferentially with blood vessels, it is conceivable that enhanced vascular clearance of Aβ1-40 contributes to the mechanisms by which CD36 deletion reduces CAA.…”

Section: Discussionmentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 99%

Innate immunity receptor CD36 promotes cerebral amyloid angiopathy

Park

Zhou

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

133

View full text Add to dashboard Cite

show abstract

“…This process takes place with coexistence of APOE ε4. Third, the vessel wall is disrupted and APOE ε2 contributes to the increase in this pathological process [6,7,9,29,30,40,49].…”

Section: Neuropathology Of Vessels With β β-Amyloid Depositsmentioning

confidence: 99%

“…Cerebral amyloid angiopathy (CAA) refers to deposition of congophilic material in the cerebral vasculature, particularly small and medium-sized arteries, capillaries and veins of leptomeninges and the cerebral cortex [1][2][3][4][5][6][7][8][9] (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

The development of cerebral amyloid angiopathy in cerebral vessels. A review with illustrations based upon own investigated post mortem cases

Mendel¹,

Wierzba-Bobrowicz²,

Lewandowska³

et al. 2013

pjp

View full text Add to dashboard Cite

The process of β-amyloid accumulation in cerebral vessels is presented. Cerebral amyloid angiopathy (CAA) was confirmed during an autopsy. It was diagnosed according to the Boston criteria. Cerebral amyloid angiopathy can involve all kinds of cerebral vessels (cortical and leptomeningeal arterioles, capillaries and veins). The development of CAA is a progressive process. β-amyloid appears first in the tunica media, surrounding smooth muscle cells, and in the adventitia. β-amyloid is progressively accumulated, causing a gradual loss of smooth muscle cells in the vessel wall and finally replacing them. Then, the detachment and delamination of the outer part of the tunica media results in the "double barrel" appearance, fibrinoid necrosis, and microaneurysm formation. Microbleeding with perivascular deposition of erythrocytes and blood breakdown products can also occur. β-amyloid can also be deposited in the surrounding of the affected vessels of the brain parenchyma, known as "dysphoric CAA". Ultrastructurally, when deposits of amyloid fibers were localized in or outside the arteriolar wall, the degenerating vascular smooth muscle cells were observed. In the Institute of Psychiatry and Neurology the study was carried out in a group of 48 patients who died due to intracerebral hemorrhage caused by sporadic CAA.

show abstract

“…It has been proven that NEP inhibitor injection and/or NEP knockout mice showed decreased Aβ degradation and a decline in cognitive activities, while its overexpression had resulted in improved spatial memory and decreased Aβ levels (Miners et al, 2011). Decreased levels of somatostain, a peptide neurotransmitter are found in the AD brain, involved in regulating NEP expression (Saito et al, 2005).…”

Section: Neprilysin (Nep)mentioning

confidence: 99%