Morphological differentiation and proteoglycan synthesis regulate Alzheimer amyloid precursor protein processing in PC‐12 and human astrocyte cultures

Baskin, Fred; Rosenberg, R. N.; Davis, Richard M.

doi:10.1002/jnr.490320217

Cited by 16 publications

(4 citation statements)

References 26 publications

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“…As oxidative damage has been linked to the accumulation of the Ab and tau proteins (Galasko and Montine 2010;Shao et al 1997), it is possible that damage to astrocytes in AD is linked to the damage to neuronal cells. The astrocyte DNA damage in response to oxidative stress varies widely during brain aging and may be an early event in the pathogenesis of Alzheimer-type pathology (Baskin et al 1992;Kitamura 1998;Ma 1987;Simpson et al 2010a, b). Normal astrocytes can degrade Ab, suggesting that abnormal astrocytes damaged by oxidative stress can increase Ab generation and accumulation.…”

Section: Activated Microglia and Astrocyte By Oxidative Damage Up-regmentioning

confidence: 99%

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

2011

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Oxidative stress has been proposed to be an important factor in the pathogenesis of Alzheimer's disease (AD) and contributed to β-amyloid (Aβ) generation. Interaction between oxidative stress and neuro-inflammation leads to Aβ generation. AD is associated with an increase in blood-brain barrier (BBB) permeability due to tight junction involvement. Oxidative stress decreases the expression of low-density lipoprotein receptor-related protein 1 and up-regulates receptor for advanced glycation end products in BBB and increases the BBB permeability, which could potentially lead to increased deposition of Aβ within AD brain. Apoptosis takes place in the pathogenesis of AD, and oxidative stress contributes to apoptosis through both extrinsic pathway and intrinsic pathway. Oxidative stress-induced apoptosis may be a potential factor to Aβ generation. Aβ generation requires two sequential cleavages of APP, with the two proteolytic enzymes: β-secretase and γ-secretase. Oxidative damage up-regulates Aβ via inducing activity of β- and γ-secretases. In this review, we will focus on the mechanism and pathway that oxidative stress contributes to Aβ generation.

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Section: Activated Microglia and Astrocyte By Oxidative Damage Up-regmentioning

confidence: 99%

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

2011

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“…Environmental or other nongenetic factors can activate ␣ secretase in sporadic AD, reducing levels of A␤. 28 The insulin-like degrading enzyme insulysin, neprolysin, and other enzymes as cathepsins are important for ␤ amyloid degradation and clearance. 29 A balance between rates of A␤ synthesis and its degradation and removal from brain is a central research issue in late-onset AD.…”

Section: Arch Gen Psychiatry 2005;62:1186-1192mentioning

confidence: 99%

Translational Research on the Way to Effective Therapy for Alzheimer Disease

Rosenberg¹

2005

Arch Gen Psychiatry

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“…Other factors also play a role. 20 However, altered turnover or removal of A␤ may also be an important event. Importantly, neuritic amyloid-containing plaques are not innocent: fibrillar A␤ is neurotoxic in vitro and in vivo.…”

Section: The Molecular and Genetic Basis Of Admentioning

confidence: 99%

The molecular and genetic basis of AD: The end of the beginning

Rosenberg

2000

Neurology

138

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The Decade of the Brain-the 1990s-was a time of gains in our knowledge of the molecular and genetic basis of Alzheimer's disease (AD). [1][2][3][4] The momentum of discovery and depth of molecular information that developed during that time clearly leads one to predict that it is the end of the beginning of deciphering the pathogenesis of AD leading to effective therapy. Most cases of AD are sporadic; however, the molecular and genetic information of specific genes and other risk factors that cause the familial form of AD will shed light on the etiology of the much more abundant sporadic forms. About 10% of familial disease presents as an autosomal dominant mode of transmission. Epidemiologic studies indicate that about 30% of AD patients have a family history of disease in which at least one first-degree relative is affected. It is clear that early onset autosomal dominant AD is a heterogeneous set of disorders caused in separate families by different genetic mutations. Late-onset sporadic disease is the result of yet-to-bediscovered multiple environmental and genetic influences. In support of this view, only one-third of identical twins are concordant for AD, indicating that nongenetic-perhaps environmental-factors are important in the pathogenesis of AD. Mutations in the amyloid precursor protein gene (APP) on chromosome 21q, and the presenilin 1 and 2 genes (PS1, PS2) on chromosomes 14q and 1q, account for approximately one half of early-onset forms of autosomal dominant inherited disease. An additional locus on chromosome 12 has also been described. It is estimated that 50% of dominantly inherited disease remains yet to be mapped and genetically identified. Although the specific functions of the proteins coded by the APP and the PS1 and PS2 genes are only incompletely known, they share a common effect of abnormally processing APP, resulting in a 50% increase in A␤ 40 or A␤ 42 peptides, which subsequently aggregate to form the neuritic plaque in the AD patient's brain. 1-4 The increased A␤ synthesis and aggregation constitute a toxic gain-of-function (gain of aggregation) that is characteristic of autosomal dominant genetic disease. These points form the genetic basis for the amyloid hypothesis.Amyloid hypothesis. The primary role of altered amyloidogenesis in the causation of AD has been supported convincingly by data of Selkoe, [5][6][7][8][9][10][11][12][13] 14 Goldgaber et al., 15 Tanzi et al., 16 Masters et al., 17 Kowal et al., 18 and Geula et al.,19 among others. The amyloid hypothesis has achieved more than a critical mass of scientific data so it is now appropriately a central construct of AD pathogenesis. An increased synthesis of A␤ from APP in the early-onset forms of AD due to APP and PS1 and PS2 mutations is a central point in support of the amyloid hypothesis, which states that abnormal amyloidogenesis or amyloid clearance are primarily causal of the pathogenesis of AD. Other molecular pathologies are of secondary importance. A more cautious view would be to say that amyloid deposition is neces...

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Morphological differentiation and proteoglycan synthesis regulate Alzheimer amyloid precursor protein processing in PC‐12 and human astrocyte cultures

Cited by 16 publications

References 26 publications

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

Translational Research on the Way to Effective Therapy for Alzheimer Disease

The molecular and genetic basis of AD: The end of the beginning

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