Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP

Li, Liang; Zhang, Xiaojie; Yang, Dehua; Luo, Guangrui; Chen, Sheng; Le, Weidong

doi:10.1016/j.neurobiolaging.2007.10.011

Cited by 196 publications

(178 citation statements)

References 31 publications

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“…OSA-related hypoxia might also contribute to amyloid deposition [13][14][15]34]. Hypoxia upregulates ␤-secretase activity, which can promote A␤ formation [13,14], and decreases neprilysin, important in A␤ clearance [15].…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia upregulates ␤-secretase activity, which can promote A␤ formation [13,14], and decreases neprilysin, important in A␤ clearance [15]. Effects of hypoxia mediated through hypoxia-inducible factor 1-alpha, can increase ␤-site amyloid precursor protein cleaving enzyme gene expression, protein level and ␤-secretase activity, resulting in a significant increase of A␤ generation [12,13].…”

Section: Discussionmentioning

confidence: 99%

“…Sleep disruption due to repetitive cortical arousals in OSA may impair sleep-dependent clearance of amyloid in interstitial fluid [10,11]. Furthermore, in vitro and in vivo experiments demonstrate that acute or sustained exposure to hypoxia/ischemia increases ␤-secretase activity, causing overproduction of amyloid-␤ (A␤), and decreased clearance by reducing neprilysin [12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

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Amyloid Burden in Obstructive Sleep Apnea

Yun

Lee

et al. 2017

JAD

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Abstract. To test the hypothesis that excessive amyloid deposition is a biological link between obstructive sleep apnea (OSA) and Alzheimer's disease, we determined whether OSA increases cerebral amyloid burden, relative to controls, using Pittsburgh Compound B (PiB) PET imaging. The subjects were adult participants (age 50-65 years) from the Korean Genome and Epidemiology Study. Polysomnography, brain MRI including 3D images, and a detailed neuro-cognitive function test battery were done in 2011-2012. Nineteen OSA subjects (Apnea-Hypopnea Index [AHI] ≥15/h, 21.2 ± 5.1/h; age 58.5 ± 4.1 years; 9 male) and 19 controls (AHI 1.8 ± 1.3/h; age 58.5 ± 4.2 years; 9 male) underwent 60-min dynamic 11 C-PiB PET. All subjects were right-handed with normal cognitive function and brain MRI. Controls were matched by age, gender, education, and APOE genotype. A voxel-wise comparison of PiB-PET images between the two groups was performed after spatial and count normalization with cerebellar gray matter as a reference. Covariates included the status of sleep duration, hypertension, diabetes, body mass index, exercise, depressive mood, smoking, and alcohol drinking. Cortical thickness on 3D MRI was also measured and compared between the two groups. The OSA group showed a higher PiB deposition in the right posterior cingulate gyrus and right temporal cortex (corrected p < 0.05). There was no area of higher uptake in the control compared with OSA. Regional differences in cortical thickness were not significant. The study suggests that OSA accelerates amyloid deposition and may contribute to the development or progression of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Amyloid Burden in Obstructive Sleep Apnea

Yun

Lee

et al. 2017

JAD

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“…On the other hand, the level and activity of β-secretase (BACE-1), an enzyme that participates of the breakdown of APP through the amyloidogenic pathway, are both increased by the upregulation of hypoxia-inducible factor 1α (HIF-1-α) caused by hypoxia [86][87][88]. Additionally, zinc metalloproteinase neprilysin (NEP), an enzyme that cleaves Aβ, is downregulated by hypoxia [89].…”

Section: Hypoxia Induced By Sleep Disordered Breathing (Sdb) Emamianmentioning

confidence: 99%

Is Sleep Disruption a Risk Factor for Alzheimer’s Disease?

Macedo

Balouch

Tabet

2017

JAD

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Sleep disturbances are routinely encountered in Alzheimer's disease (AD) and affect about 25-40% of patients in the mild-to-moderate stages of the disease. In many, sleep pathology may represent a symptom of the underlying neurodegeneration. However, a history of sleep disruption occurring years prior to onset of cognitive symptoms could represent a potential risk factor for AD. The aim of the present narrative review was to evaluate current evidence linking sleep disturbances with AD development and to understand the mechanisms that may contribute to this.Although the mechanisms by which poor sleep may contribute to AD genesis is not fully understood, emerging evidence linking disturbances in the sleep wake cycle with Aβ deposition is shedding light on the relationship between sleep pathology and the subsequent development of AD. Aβ burden appears to be enhanced by sleep-wake cycle disruptions and is suspected as being an important mechanism by which sleep disruptions contribute in AD development. Other mechanisms triggered by sleep disruption may also be involved in AD development, such as brain hypoxia, oxidative stress, circadian activity rhythms disturbances, overexpression of orexins and blood brain barrier impairment. Further understanding of the link between sleep disturbances and future development of AD is still needed before sleep disturbances are clearly marked as a preventable risk factor for AD. In these circumstances, early lifestyle interventions to help increase the quantity and quality of sleep may have a favorable outcome on decreasing the incidence of AD and this needs to be investigated further.

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“…В усло-виях гипоксии ткани происходит более быстое фор-мирование β-амилоида из АРР в связи с нарушением регуляции активности ферментов β-и γ-секретазы, обеспечивающих метаболизм данного белка [24][25][26]. Важная роль гипоперфузии в отложении β-амилоида подтверждена на экспериментальных моделях.…”

Section: β-амилоид и сосудистые факторы рискаunclassified

Twenty-five years of the amyloid hypothesis of alzheimer disease: advances, failures and new perspectives

Левин¹,

Васенина²

2016

Z. nevrol. psikhiatr. im. S.S. Korsakova

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115 лет назад -25 ноября 1901 г. -51-летняя женщина А. Дитер была доставлена во Франкфурт-скую муниципальную лечебницу «для лунатиков и эпилептиков», где обратила на себя внимание 37-летнего психиатра А. Альцгеймера (1864-1915) необычными для ее возраста быстро нарастающими нарушениями памяти, речи, параноидными рас-стройствами. 110 лет назад -в 1906 г. Альцгеймер на заседании общества психиатров юго-запада Гер-мании в Тюбенгене представил сообщение о клини-ческих проявлениях и патоморфологических наход-ках, выявленных у умершей к тому времени паци-ентки. При аутопсии с помощью разработанной не-давно методики импрегнации серебром А. Альцгей-doi: 10.17116/jnevro2016116623-9 25 лет амилоидной гипотезе происхождения болезни Альцгеймера: достижения, неудачи и новые перспективы О.С. ЛЕВин*, Е.Е. ВаСЕнина ГБОУ ДПО «Российская медицинская академия последипломного образования», Москва, Россия амилоидная гипотеза развития болезни альцгеймера (Ба) продолжает доминировать, однако за свою 25-летнюю историю концепция значительно изменилась. Оказалось, что накопление β-амилоида связано не только с повышением его продукции (как казалось после открытия генетических механизмов части семейных случаев Ба), но и с нарушением его клиренса из ткани головного мозга, который осуществляется при помощи микроциркуляторной системы. При этом наиболее патогенную роль в веществе мозга играют не сами сенильные бляшки, описанные а. альцгеймером почти 110 лет назад и состоящие из нерастворимых конъюгатов, а растворимые олигомеры β-амилоида. Связь сосудистого и дегенеративного процессов при Ба подтверждают единство факторов риска, а также клинические, нейровизуализацион-ные, патоморфологические и экспериментальные данные. Одним из звеньев, связующих дегенеративный и сосудистый процессы при Ба, служит инсулинорезистентность. исходя из современного состояния амилоидной гипотезы обсуждаются вопросы новых мультимодальных стратегий терапии Ба. Ключевые слова: β-амилоид, болезнь Альцгеймера, артериосклероз, инсулинорезистентность, мультимодальная терапия. Twenty-five years of the amyloid hypothesis of Alzheimer's disease: advances, failures and new perspectivesO.S. Levin, e.e. vaSenina Russian Medical academy of Postgraduate education, Moscow, Russia amyloid hypothesis of alzheimer's disease (aD) has been long the primary one. During the 25-year history the concept has been dramatically changed. accumulation of β-amyloid is associated not only with the disruption of its synthesis (as it seemed after the discovery of genetic mechanisms of some familial cases of aD) but rather with the disruption of its clearance and elimination from the brain tissue via the microcirculatory system. it has been recognized that soluble oligomers of β-amyloid, but not senile plaques that consisted of insoluble conjugates described by a. alzheimer 100 years ago, play a key pathogenic role in the brain. interrelation of vascular and degenerative processes is confirmed by common risk factors, clinical, neuroimaging, pathomorphological and experimental data. insulin-resis...

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Hypoxia increases Aβ generation by altering β- and γ-cleavage of APP

Cited by 196 publications

References 31 publications

Amyloid Burden in Obstructive Sleep Apnea

Amyloid Burden in Obstructive Sleep Apnea

Is Sleep Disruption a Risk Factor for Alzheimer’s Disease?

Twenty-five years of the amyloid hypothesis of alzheimer disease: advances, failures and new perspectives

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