Insights into the physiological function of the β‐amyloid precursor protein: beyond Alzheimer's disease

Dawkins, Edgar; Small, David H.

doi:10.1111/jnc.12675

Cited by 219 publications

(167 citation statements)

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“…For example, APP is expressed in developing neuroblasts at the time of cell proliferation and differentiation (26,31,41). In the present study we found that in the absence of APP, there was a decrease in NSPC differentiation into neurons.…”

Section: Discussionsupporting

confidence: 60%

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Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Bolós

Young

et al. 2014

Journal of Biological Chemistry

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Background: Amyloid-␤ precursor protein is implicated in neural stem cell development. Results: Neurogenin 2 expression and neuronal differentiation correlated with amyloid-␤ precursor protein expression in neural stem/progenitor cells. Conclusion: Amyloid-␤ precursor protein regulates neuronal differentiation by altering neurogenin 2 expression. Significance: The study provides a new mechanism to explain the effects of amyloid-␤ precursor protein on neural stem cell differentiation.

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Section: Discussionsupporting

confidence: 60%

“…Emerging evidence suggests that APP plays a role in neuronal growth and neural repair, although the precise mechanisms have been unclear (31). The expression of APP is regulated developmentally (28,32) and is increased in association with neurite outgrowth and synaptogenesis (8,26).…”

Section: Discussionmentioning

confidence: 99%

Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Bolós

Young

et al. 2014

Journal of Biological Chemistry

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“…PME-1 and LCMT-1 bidirectionally altered both the electrophysiological and behavioral responses to nanomolar Aβ administration, without affecting baseline LTP, behavioral performance, or the ability of the administration of 200 pM Aβ to enhance LTP. Given that normal physiological levels of Aβ play an important role in regulating neuronal activity (35,(42)(43)(44), this ability to target Aβ's pathological actions selectively could provide an approach that reduces AD-related impairments without interfering with normal nervous system function. Identifying the molecules acting downstream of PP2A in this process also will help clarify the molecular mechanisms by which Aβ exerts its pathological effects.…”

Section: Discussionmentioning

confidence: 99%

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Nicholls

Sontag

Zhang

et al. 2016

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

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Elevated levels of the β-amyloid peptide (Aβ) are thought to contribute to cognitive and behavioral impairments observed in Alzheimer's disease (AD). Protein phosphatase 2A (PP2A) participates in multiple molecular pathways implicated in AD, and its expression and activity are reduced in postmortem brains of AD patients. PP2A is regulated by protein methylation, and impaired PP2A methylation is thought to contribute to increased AD risk in hyperhomocysteinemic individuals. To examine further the link between PP2A and AD, we generated transgenic mice that overexpress the PP2A methylesterase, protein phosphatase methylesterase-1 (PME-1), or the PP2A methyltransferase, leucine carboxyl methyltransferase-1 (LCMT-1), and examined the sensitivity of these animals to behavioral and electrophysiological impairments caused by exogenous Aβ exposure. We found that PME-1 overexpression enhanced these impairments, whereas LCMT-1 overexpression protected against Aβ-induced impairments. Neither transgene affected Aβ production or the electrophysiological response to low concentrations of Aβ, suggesting that these manipulations selectively affect the pathological response to elevated Aβ levels. Together these data identify a molecular mechanism linking PP2A to the development of AD-related cognitive impairments that might be therapeutically exploited to target selectively the pathological effects caused by elevated Aβ levels in AD patients.M ultiple observations suggest a role for the serine/threonine protein phosphatase 2A (PP2A) in the molecular pathways that underlie Alzheimer's disease (AD). Analyses conducted on postmortem AD brains have found reduced PP2A expression and activity, and studies conducted in animal models have found that inhibiting PP2A produces AD-like tau pathology and cognitive impairment (1-3). One of the ways in which PP2A may affect AD is through its role as the principal tau phosphatase (4-7). PP2A also interacts with a number of kinases implicated in AD including glycogen synthase kinase 3β (GSK3β), cyclindependent kinase 5 (CDK5), and ERK and JNK as well as amyloid precursor protein and the NMDA and metabotropic glutamate receptors (reviewed in ref.2).PP2A is a heterotrimeric protein composed of a catalytic, scaffolding, and regulatory subunit. Each subunit is encoded by multiple genes and splice isoforms, and the subunit composition of a particular PP2A molecule determines its subcellular distribution and substrate specificity (reviewed in ref.2). One of the ways in which PP2A activity is regulated is through C-terminal methylation of the catalytic subunit (reviewed in refs. 8 and 9). Impaired methyl-donor metabolism is a risk factor for AD (10, 11), and PP2A dysregulation caused by impaired methylation is thought to be one of the molecular mechanisms contributing to this increased risk (12)(13)(14). Methylation promotes the formation of PP2A holoenzymes that contain Bα regulatory subunits (7,13,(15)(16)(17)(18)(19), and these forms of PP2A exhibit the greatest tau phosphatase activity (6, 7).PP2A m...

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“…Эта точка зрения подтверждается данными [26], показывающими, что со-вместное удаление генов APP и APLP2, либо двух APLP, либо всех трех членов семейства приводит к ранней пост-натальной смерти. Экспериментальные данные показы-вают, что APP играет важную роль в процессах клеточного роста и пролиферации, а также может служить трофиче-ским фактором, влияя на рост отростков нейронов (ней-риты) и синаптогенез [27].…”

Section: роль аβ в патогенезе баunclassified

Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer’s disease

Kukharsky

2015

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

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Болезнь Альцгеймера (БА) -наиболее распростра-ненная форма деменции среди пожилых людей [1][2][3]. Клинические симптомы БА на начальных стадиях вклю-чают прежде всего нарушение памяти, особенно потерю информации о недавних событиях, на более поздних ста-диях, помимо существенного ухудшения памяти и прак-тической неспособности к обучению, присоединяются эмоциональные расстройства, дефектность речи, сниже-ние интеллекта, деградация личности. В конечном итоге пациент не может выполнить даже самые простые задачи, такие как поддержание личной гигиены, не может себя обслуживать и становится полностью социально зависи-мым.Основным фактором риска развития деменции явля-ется возраст: каждые 5 лет после 65-летнего возраста риск заболевания удваивается.В мире насчитывается более 35 млн человек, страдаю-щих БА [4]. К середине века ее распространенность в США, по прогнозам экспертов [2], увеличится почти в 4 раза и будет соответствовать 1 больному на 45 человек.После постановки первоначального диагноза средняя продолжительность жизни составляет от 5 до 10 лет, хотя пациенты с БА могут жить и дольше -до 20 лет [5]. Вели- This review addresses the current hypotheses of the pathogenesis of Alzheimer's disease (AD) and methods of its pharmacological correction. The following topics are reviewed: a role of β-amyloid in the pathogenesis of AD, a role of tau-protein in the pathogenesis of AD, main hypotheses of the pathogenesis, the relationship between β-amyloid and tau-protein, the dysfunction of synapses in AD, a neuroimmune hypothesis, treatment approaches. Alzheimer's disease, β-amyloid, tau-protein. ка вероятность, что БА будет оставаться клиническим, со-циальным и экономическим бременем на протяжении продолжительного времени. В настоящее время не разработана эффективная тера-пия деменций. Это связано прежде всего с тем, что до сих пор, несмотря на значительный прогресс в нейробиоло-гии и медицине за последние несколько десятилетий, не изучен патогенез этого заболевания. Остается неясной и его этиология. Удалось выявить лишь важнейшие состав-ляющие патогенеза БА, в том числе на молекулярном уровне [6]. Согласно современным представлениям БА является протеинопатией, развивающейся вследствие на-рушения метаболизма белка -предшественника амилои-да и тау-белка [7][8][9]. Ключевым патологическим событи-ем является потеря белком его нормальной конформации, что приводит к накоплению олигомеров, состоящих из нескольких пептидов, которые в свою очередь объединят-ся в промежуточные формы агрегатов и, наконец, образу-ют нерастворимые агрегаты. Растворимые олигомеры и промежуточные продукты агрегации являются наиболее токсичными для нервных клеток, тогда как конечные продукты агрегации относительно инертны. Это харак-терно как для β-амилоида (Аβ), так и для тау-белка [10,11]. Keywords: Alzheimer's disease, pathogenesis of Alzheimer's disease, treatment of

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Insights into the physiological function of the β‐amyloid precursor protein: beyond Alzheimer's disease

Cited by 219 publications

References 203 publications

Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

Neurogenin 2 Mediates Amyloid-β Precursor Protein-stimulated Neurogenesis

PP2A methylation controls sensitivity and resistance to β-amyloid–induced cognitive and electrophysiological impairments

Molecular aspects of the pathogenesis and current approaches to pharmacological correction of Alzheimer’s disease

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