Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Hawkes, Cheryl A.; Gatherer, Maureen; Sharp, Matthew MacGregor; Dorr, Adrienne; Yuen, Ho Ming; Kalaria, Rajesh N.; Weller, Roy O.; Carare, Roxana O.

doi:10.1111/acel.12045

Cited by 122 publications

(154 citation statements)

References 51 publications

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“…38,39 Presence of severe WMH may reflect impaired perivascular drainage in the setting of severe CAA, with stasis of interstitial fluid, and chronic white matter edema. 40,e1 In addition, severe subcortical small-vessel disease (encompassing lacunar infarction and WMH) may act in concert with CAA to increase risk of LMBs.…”

Section: Resultsmentioning

confidence: 99%

Incidence of cerebral microbleeds in preclinical Alzheimer disease

et al. 2014

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Objective: We sought to determine the incidence and associations of lobar microbleeds (LMBs) in a longitudinal cohort with 11 C-Pittsburgh compound B (PiB) PET imaging.Methods: One hundred seventy-four participants from the observational Australian Imaging, Biomarkers and Lifestyle Study of Ageing (97 with normal cognition [NC], 37 with mild cognitive impairment [MCI], and 40 with Alzheimer disease [AD] dementia) were assessed at 3 time points over 3 years with 3-tesla susceptibility-weighted MRI and 11 C-PiB PET. MRIs were inspected for microbleeds, siderosis, infarction, and white matter hyperintensity severity, blind to clinical and PiB findings. Neocortical PiB standardized uptake value ratio, normalized to cerebellar cortex, was dichotomized as positive or negative (PiB1/2, standardized uptake value ratio .1.5). Annualized LMB incidence was calculated, and logistic regression was used to determine the association of incident LMBs with PiB, APOE e41 status, and cerebrovascular disease.Results: LMBs were present in 18.6% of NC, 24.3% of MCI, and 40% of AD participants (p , 0.05 vs NC). LMB incidence was 0.2 6 0.6 per year in NC participants, 0.2 6 0.5 in MCI, and 0.7 6 1.4 in AD (p , 0.03 vs NC) and was 6-fold higher in PiB1 than PiB-NC. Incident LMBs were associated with age, APOE e41, PiB1, and baseline LMBs. Incidence of multiple LMBs was also associated with lacunar infarction and white matter hyperintensity severity. Conclusions:Older age, baseline LMBs, higher b-amyloid burden, and concomitant cerebrovascular disease may all confer higher risk of incident LMBs. This should be considered when designing protocols for amyloid-modifying clinical trials. Neurology ® 2014;82:1266-1273 GLOSSARY Ab 5 b-amyloid; AD 5 Alzheimer disease; AIBL 5 Australian Imaging, Biomarkers and Lifestyle Study of Ageing; CAA 5 cerebral amyloid angiopathy; CI 5 confidence interval; FLAIR 5 fluid-attenuated inversion recovery; GRE 5 gradient-recall echo; LMB 5 lobar microbleed; MCI 5 mild cognitive impairment; MP-RAGE 5 magnetization-prepared rapid-acquisition gradient echo; NC 5 normal cognition; OR 5 odds ratio; PiB 5 Pittsburgh compound B; SS 5 superficial siderosis; SUVR 5 standardized uptake value ratio; SWI 5 susceptibility-weighted imaging; TE 5 echo time; TR 5 repetition time; VRF 5 vascular risk factor; WMH 5 white matter hyperintensity.

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Section: Resultsmentioning

confidence: 99%

Incidence of cerebral microbleeds in preclinical Alzheimer disease

et al. 2014

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“…32 They are key components of the BBB and they have been shown to be implicated in drainage of Ab. 9,31 Perlecan and fibronectin have been proposed to participate in Ab accumulation by accelerating its aggregation by providing a higher stability of Ab in the basement membrane. 10,11 Interestingly, perlecan and fibronectin levels are also elevated during aging in mice, and this could in part explain the impaired drainage of Ab in the aging brain.…”

Section: Discussionmentioning

confidence: 99%

“…10,11 Interestingly, perlecan and fibronectin levels are also elevated during aging in mice, and this could in part explain the impaired drainage of Ab in the aging brain. 9,31 However, whereas perlecan is normally expressed in abundance around healthy cerebral blood vessels, it is absent around amyloid-laden blood vessels in the brains of Alzheimer's disease and hereditary cerebral hemorrhage with amyloidosis of the Dutch-type patients, 33 raising the intriguing possibility that diminished perivascular perlecan expression could contribute to cerebral amyloid angiopathy. Our observations suggest that jTBI-induced expression of perlecan and fibronectin participate in the establishment of accelerated brain aging.…”

Section: Discussionmentioning

confidence: 99%

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Jullienne

Roberts

Pop

et al. 2014

J Cereb Blood Flow Metab

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In our juvenile traumatic brain injury (jTBI) model, emergence of cognitive dysfunctions was observed up to 6 months after trauma. Here we hypothesize that early brain injury induces changes in the neurovascular unit (NVU) that would be associated with amyloid-beta (Ab) accumulation. We investigated NVU changes for up to 6 months in a rat jTBI model, with a focus on the efflux protein P-glycoprotein (P-gp) and on the basement membrane proteins perlecan and fibronectin, all known to be involved in Ab clearance. Rodent-Ab staining is present and increased after jTBI around cerebral blood microvessels, and the diameter of those is decreased by 25% and 34% at 2 and 6 months, respectively, without significant angiogenesis. P-glycoprotein staining in endothelium is decreased by 22% and parallels an increase of perlecan and fibronectin staining around cerebral blood vessels. Altogether, these results strongly suggest that the emergence of long-term behavioral dysfunctions observed in rodent jTBI may be related to endothelial remodeling at the blood-brain barrier alongside vascular dysfunction and altered Ab trafficking. This study shows that it is important to consider jTBI as a vascular disorder with long-term consequences on cognitive functions.

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“…Several other effects of hypertension may also play a role. These could include impaired perivascular drainage as a consequence of collagenous thickening and reduced pulsatility of arteries and arterioles [48][49][50]; reduced receptor-mediated transport of Aβ across the endothelium into the bloodstream; degeneration of pericytes [51], leading to reduced clearance of soluble Aβ40 and Aβ42 from the interstitial fluid [52];…”

Section: Groups (Supplementarymentioning

confidence: 99%

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

Ashby

Miners

Kehoe

et al. 2016

JAD

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Epidemiological data associate hypertension with a predisposition to Alzheimer's disease (AD) and a number of post-mortem and in vivo studies also demonstrate that hypertension increases amyloid-beta (Aβ) pathology. In contrast anti-hypertensive medications reportedly improve cognition and decrease the risk of AD, while certain classes of anti-hypertensive drugs are associated with decreased AD-related pathology. We investigated the effects of hypertension and anti-hypertensive treatment on Aβ plaque load in post-mortem frontal cortex in AD. Aβ load was significantly increased in hypertensive (N = 20) relative to normotensive cases (N = 62) and was also significantly higher in treated (N = 9) than untreated hypertensives (N = 11). We then looked into mechanisms by which hypertension and treatment might increase Aβ load, focusing on Aβ-synthesising enzymes, β-and γ-secretase, and Aβ-degrading enzymes, angiotensin-converting enzyme (ACE), insulin-2 degrading enzyme (IDE) and neprilysin. ACE and IDE protein levels were significantly lower in hypertensive (N = 21) than normotensive cases (N = 64), perhaps translating to decreased Aβ catabolism in hypertensives. ACE level was significantly higher in treated (N = 9) than untreated hypertensives (N = 12), possibly reflecting feedback upregulation of the reninangiotensin system. Prospective studies in larger cohorts stratified according to antihypertensive drug class are needed to confirm these initial findings and to elucidate the interactions between hypertension, anti-hypertensive treatments and Aβ metabolism.Keywords: Alzheimer's disease, amyloid β protein, anti-hypertensive, hypertension, β-secretase, BACE, γ-secretase, angiotensin-converting enzyme, insulin-degrading enzyme Abbreviations: Aβ = amyloid-beta; AβPP = amyloid-beta precursor protein; ACE = angiotensin-converting enzyme; ACEI = angiotensin-converting enzyme inhibitor; AD = Alzheimer's disease; AngII = angiotensin II; ARB = angiotensin receptor blocker; BBB = blood brain barrier; CCB = calcium channel blocker; IDE = insulin-degrading enzyme; NEP = neprilysin; NFT = neurofibrillary tangle

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Regional differences in the morphological and functional effects of aging on cerebral basement membranes and perivascular drainage of amyloid‐β from the mouse brain

Cited by 122 publications

References 51 publications

Incidence of cerebral microbleeds in preclinical Alzheimer disease

Incidence of cerebral microbleeds in preclinical Alzheimer disease

Juvenile Traumatic Brain Injury Induces Long-Term Perivascular Matrix Changes Alongside Amyloid-Beta Accumulation

Effects of Hypertension and Anti-Hypertensive Treatment on Amyloid-β (Aβ) Plaque Load and Aβ-Synthesizing and Aβ-Degrading Enzymes in Frontal Cortex

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