Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse

Shang, Jingwei; Yamashita, Toru; Tian, Feng; Li, Xianghong; Liu, Xia; Shi, Xiaowen; Nakano, Yumiko; Tsunoda, Keiichiro; Nomura, Emi; Sasaki, Ryo; Tadokoro, Koh; Sato, Kota; Takemoto, Mami; Hishikawa, Nozomi; Ohta, Yasuyuki; Abe, Kōji

doi:10.1016/j.brainres.2019.146379

Cited by 33 publications

(27 citation statements)

References 34 publications

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“…Furthermore, we investigated expressive changes of two main Aβ transport receptors, LRP-1 and RAGE, and revealed that CCH increased LRP-1 and RAGE expression in brain parenchyma, while a decrease of LRP1 and increase of RAGE were observed in vascular endothelial cells, suggesting double imbalances of Aβ efflux and influx transport-related proteins in the cortical blood vessel of AD mice. These neuropathological abnormalities were greatly ameliorated by edaravone [87].…”

Section: Chronic Cerebral Hypoperfusionmentioning

confidence: 99%

Prevention of Cognitive Decline in Alzheimer’s Disease by Novel Antioxidative Supplements

Tadokoro

Ohta

Inufusa

et al. 2020

IJMS

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Oxidative stress plays a crucial role in Alzheimer's disease (AD) from its prodromal stage of mild cognitive impairment. There is an interplay between oxidative stress and the amyloid β (Aβ) cascade via various mechanisms including mitochondrial dysfunction, lipid peroxidation, protein oxidation, glycoxidation, deoxyribonucleotide acid damage, altered antioxidant defense, impaired amyloid clearance, inflammation and chronic cerebral hypoperfusion. Based on findings that indicate that oxidative stress plays a major role in AD, oxidative stress has been considered as a therapeutic target of AD. In spite of favorable preclinical study outcomes, previous antioxidative components, including a single antioxidative supplement such as vitamin C, vitamin E or their mixtures, did not clearly show any therapeutic effect on cognitive decline in AD. However, novel antioxidative supplements can be beneficial for AD patients. In this review, we summarize the interplay between oxidative stress and the Aβ cascade, and introduce novel antioxidative supplements expected to prevent cognitive decline in AD.

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Section: Chronic Cerebral Hypoperfusionmentioning

confidence: 99%

Prevention of Cognitive Decline in Alzheimer’s Disease by Novel Antioxidative Supplements

Tadokoro

Ohta

Inufusa

et al. 2020

IJMS

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“…Many studies have shown that cerebral hypoperfusion signi cantly increases β-and γsecretase activity, consequently increasing Aβ production in the brain [5,6,19]. In addition to increased Aβ generation, hypoperfusion affects peptidases that degrade Aβ peptides, thus reducing Aβ clearance [20,21]. Aβ deposition in small arteries caused by cerebral hypoperfusion could further induce cerebrovascular lesions and worsen cerebral hypoperfusion, nally leading to a vicious cycle and irreversible damage [22,23].…”

Section: Discussionmentioning

confidence: 99%

Altered Amyloid-β and Tau Proteins in Neural-Derived Plasma Exosomes in Patients with Type 2 Diabetes and Orthostatic Hypotension

Zhang¹,

Chi²,

Wang³

et al. 2020

Preprint

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BackgroundEmerging evidence suggests a role for orthostatic hypotension (OH) in contributing to the progression of Alzheimer disease (AD). The aim of the study was to investigate whether neural-derived plasma exosomal amyloid-β and tau protein levels are associated with OH in diabetes mellitus (DM) patients.MethodsThere were 274 subjects without dementia included in the study: 81 control participants (controls), 101 normotensive patients with DM without OH, and 92 patients with DM and neurogenic OH (DMOH). Neuronal-derived exosomal proteins were measured by ELISA kits for amyloid-β and tau.ResultsThe neuronal-derived exosome levels of Aβ42, T-tau, and P-T181-tau in the DM with OH group were higher than those in the DM and control groups. Multivariable linear regression analysis showed that the presence of OH in patients with DM was associated with elevated exosomal Aβ42 (β = 0.172, P = 0.018), T-tau(β = 0.159, P = 0.030), and P-T181-tau (β = 0.220, P = 0.003) levels after adjustment for age, sex, APOE ε4, duration of type 2 diabetes, HbA1c and cardiovascular risk factors. Furthermore, the levels of Aβ42, T-tau, and P-T181-tau in neuronal-derived exosomes were correlated with HIF-1α levels and the drop in mean cerebral blood flow velocity from the supine to upright position.ConclusionsThe presence of OH in DM patients was independently associated with elevated the Aβ42, T-tau, and PT181-tau levels in neural-derived plasma exosomes. Cerebral hypoperfusion from DM with OH are likely candidate mechanisms.Trial registrationChinese Clinical Trial Registry (Identifier: ChiCTR1900021544 ). Registered 27 February 2019.

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“…In addition to possible innate immune clearance mechanisms, our model may impact LRP1 which mediates Aβ efflux in cerebral microvessels (Donahue et al, 2006; Kanekiyo et al, 2012) or receptor for advanced glycation end products (RAGE) in neurons which can mediate Aβ influx (Deane et al, 2003) or LDLR that can reduce Aβ (Kim et al, 2009; Katsouri and Georgopoulos, 2011). Specifically it would be important to examine redistribution of RAGE and LRP1 between microvasculature and neurons which appears Aβ or AD specific (Donahue et al, 2006; Shang et al, 2019) and increased expression of the low-density lipoprotein receptor (LDLR) which appears hypertension or SHRSP-specific (Ueno et al, 2010). However, whatever the mechanisms involved are, the Aβ effects are surprisingly small and regional and not the salient interactive feature in our model or in humans.…”

Section: Discussionmentioning

confidence: 99%

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

Denver

D'Adamo

et al. 2019

Front. Physiol.

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Alzheimer's disease (AD) and mixed dementia (MxD) comprise the majority of dementia cases in the growing global aging population. MxD describes the coexistence of AD pathology with vascular pathology, including cerebral small vessel disease (SVD). Cardiovascular disease increases risk for AD and MxD, but mechanistic synergisms between the coexisting pathologies affecting dementia risk, progression and the ultimate clinical manifestations remain elusive. To explore the additive or synergistic interactions between AD and chronic hypertension, we developed a rat model of MxD, produced by breeding APPswe/PS1 E9 transgenes into the stroke-prone spontaneously hypertensive rat (SHRSP) background, resulting in the SHRSP/FAD model and three control groups (FAD, SHRSP and non-hypertensive WKY rats, n = 8-11, both sexes, 16-18 months of age). After behavioral testing, rats were euthanized, and tissue assessed for vascular, neuroinflammatory and AD pathology. Hypertension was preserved in the SHRSP/FAD cross. Results showed that SHRSP increased FAD-dependent neuroinflammation (microglia and astrocytes) and tau pathology, but plaque pathology changes were subtle, including fewer plaques with compact cores and slightly reduced plaque burden. Evidence for vascular pathology included a change in the distribution of astrocytic end-foot protein aquaporin-4, normally distributed in microvessels, but in SHRSP/FAD rats largely dissociated from vessels, appearing disorganized or redistributed into neuropil. Other evidence of SVD-like pathology included increased collagen IV staining in cerebral vessels and PECAM1 levels. We identified a plasma biomarker in SHRSP/FAD rats that was the only group to show increased Aqp-4 in plasma exosomes. Evidence of neuron damage in SHRSP/FAD rats included increased caspase-cleaved actin, loss of myelin and reduced calbindin staining in neurons. Further, there were mitochondrial deficits specific to SHRSP/FAD, notably the loss of complex II, accompanying FADdependent loss of mitochondrial complex I. Cognitive deficits exhibited by FAD rats were not exacerbated by the introduction of the SHRSP phenotype, nor was

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Chronic cerebral hypoperfusion alters amyloid-β transport related proteins in the cortical blood vessels of Alzheimer’s disease model mouse

Cited by 33 publications

References 34 publications

Prevention of Cognitive Decline in Alzheimer’s Disease by Novel Antioxidative Supplements

Prevention of Cognitive Decline in Alzheimer’s Disease by Novel Antioxidative Supplements

Altered Amyloid-β and Tau Proteins in Neural-Derived Plasma Exosomes in Patients with Type 2 Diabetes and Orthostatic Hypotension

A Novel Model of Mixed Vascular Dementia Incorporating Hypertension in a Rat Model of Alzheimer’s Disease

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