Developmental and aging changes in the expression patterns of beta-amyloid in the brains of normal and down syndrome cases

Takashima, Sachio; Kuruta, Hiromi; Mito, Takashi; Nishizawa, Masatoyo; Kunishita, Tatsuhide; Tabira, Takeshi

doi:10.1016/s0387-7604(12)80066-0

Cited by 29 publications

(14 citation statements)

References 16 publications

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“…Interestingly, the increase in LH is higher and occurs earlier in women, who are more susceptible to AD than men. The increase in gonadotropins following menopause/andropause suggests that the neuron hormonal environment reverts back to one more akin to that of the fetal brain, which has been shown to display many similarities to AD brains, namely the presence of A␤ (75), hyperphosphorylated tau (76), and presenilin expression (77). Because the expression of these biochemical parameters is normally associated with neurogenesis, it is possible that the post-reproductive change in HPG hormones might promote abberant re-entry of neurons into the cell cycle.…”

Section: Contribution Of Sex Steroids and Gonadotropins To Amyloidosis-mentioning

confidence: 99%

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Bowen

Verdile

Liu

et al. 2004

Journal of Biological Chemistry

167

132

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Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-␤ (A␤) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether A␤ generation was due to the loss of serum 17␤-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p < 0.0001) and a 1.5-fold (p < 0.024) reduction in total brain A␤1-42 and A␤1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-␤ precursor protein (A␤PP) expression but did alter A␤PP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of A␤, decreased ␣A␤PP secretion, and increased A␤PP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote A␤ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.Alzheimer's disease (AD) 1 is a neurodegenerative disorder of the elderly that leads to progressive memory loss, impairments in behavior, language, visuo-spatial skills, and ultimately death. The one or more underlying biochemical mechanisms leading to AD are unknown. Genetic studies have shown that mutations in A␤PP and the presenilin genes lead to early onset (Յ65 years) AD, which accounts for ϳ5% of all AD cases. The vast majority of these mutations promote the overproduction and deposition of amyloid-␤ (A␤) (1-7), the major component of the extracellular amyloid plaques, in the hippocampus and frontal cortex (8,9). Amyloid deposition also is a hallmark of the late-onset or "sporadic" form of AD, which accounts for ϳ95% of AD cases. The primary factors responsible for A␤ deposition and disease progression in late onset AD remain to be elucidated.Aging, the strongest risk factor for late-onset AD, is associated with major changes in serum concentrations of all hormones that comprise the hypothalamic-pituitary-gonadal (HPG) axis, including declines in the serum concentrations of the sex steroids, 17␤-estradiol and testosterone. Such changes have been correlated with the prevalence of the disease (e.g. Refs. 10 -14), and it has been shown that there is a decreased i...

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Section: Contribution Of Sex Steroids and Gonadotropins To Amyloidosis-mentioning

confidence: 99%

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Bowen

Verdile

Liu

et al. 2004

Journal of Biological Chemistry

167

132

View full text Add to dashboard Cite

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“…Other parallels between embryonic neurogenesis and adult neurodegeneration include the expression of AβPP, secretases, and tau, together with the processing of AβPP either toward the amyloidogenic or nonamyloidogenic pathways, and the phosphorylation of tau ([39] and Atwood and Porayette, unpublished data). Similarly, the fetal brain has been reported to display a number of biochemical similarities to the AD brain, namely the presence of Aβ and AβPP [140,141], presenilin-1 expression [142], and hyperphosphorylated tau [143]. The phosphorylation of tau is a mitogenic-associated event that normally occurs during metaphase of neuronal division, and is observed during differentiation of neurons in the fetal brain [143,144].…”

Section: Alzheimer's Diseasementioning

confidence: 99%

Gonadotropins and Progestogens: Obligatory Developmental Functions during Early Embryogenesis and their Role in Adult Neurogenesis, Neuroregeneration and Neurodegeneration

Atwood

Meethal

2011

Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis

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IntroductionHormones of the hypothalamic-pituitary-gonadal (HPG) axis are well known for their roles in reproduction. However, sex hormones have roles far beyond the regulation and coordination of reproduction; they also control the entire molecular process of life from the conception of the embryo through its development into an adult and finally its demise during senescence [1]. This recent understanding of the ''big picture,'' that is, of how HPG hormones regulate life processes, has gathered support from studies identifying the function of reproductive hormones in embryonic development [2][3][4][5], as well as from studies into the extrareproductive functions of HPG hormones in the postreproductive physiology of mammals (reviewed in [6]).This chapter describes our current, albeit incomprehensively small, knowledge of how reproductive (pregnancy) hormones direct growth and development during embryogenesis. It also describes the requirement for these reproductive hormones during adult life, and how the age-related dysregulation in the signaling of these hormones drives neurodegeneration and cognitive decline during senescence. Hormonal Regulation of Human Embryogenesis The Missing LinksEmbryogenesis is a complex coordinated series of molecular and cellular changes that takes place within a well-defined internal environment. Human embryogenesis is orchestrated by a complex array of endocrine signals that commences with conception, is followed by the growth and development of the zygote into a blastocyst, its implantation into the endometrium, and the subsequent growth and development of the blastocyst into the neonate. Following conception, the Hormones in Neurodegeneration, Neuroprotection, and Neurogenesis.

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“…chromosomal replication leading to polyploidy, upregulation of cell cycle markers, tau phosphorylation, AβPP metabolism and Aβ deposition (see below), oxidative stress, increased mitochondrial DNA and Cox-1 expression, upregulated growth factor signaling pathways, synapse loss and death of differentiated neurons). Indeed, the AD brain displays many of the neuropathological and biochemical changes observed in the fetal brain, namely the presence of Aβ (Takashima, et al 1990), hyper-phosphorylated tau (Goedert et al 1993) and presenilin expression (Berezovska, et al 1997). Therefore, Aβ appears to be involved with neuron death/remodeling, just as tau phosphorylation is known to destabilize microtubules in order for neuron division to occur during development (Goedert et al 1993; Liu et al 2004).…”

Section: Gonadotropins Gnrh1 and Cell Cycle Abnormalities In Alzhmentioning

confidence: 99%

“…There are a number of morphological and biochemical similarities between the aging brain and the fetal brain including the presence of Aβ and AβPP (Arai, et al 1997; Takashima et al 1990), hyper-phosphorylated tau (Goedert et al 1993) and presenilin-1 expression (Berezovska et al 1997). This increased developmental protein expression in the AD brain suggests reactivation of the cell cycle in differentiated neurons of the AD brain (Herrup and Yang 2007) and explains the majority of the biochemical and pathological features associated with the disease (Atwood et al 2005; Meethal, et al 2005).…”

Section: Gonadotropins Gnrh1 and Cell Cycle Abnormalities In Alzhmentioning

confidence: 99%

The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

Atwood

Bowen²

2015

Hormones and Behavior

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Sex hormones are the physiological factors that regulate neurogenesis during embryogenesis and continuing through adulthood. These hormones support the formation of brain structures such as dendritic spines, axons and synapses required for the capture of information (memories). Intriguingly, a recent animal study has demonstrated that induction of neurogenesis results in the loss of previously encoded memories in animals (e.g. infantile amnesia). In this connection, much evidence now indicates that Alzheimer’s disease (AD) also involves aberrant re-entry of post-mitotic neurons into the cell cycle. Cell cycle abnormalities appear very early in the disease, prior to the appearance of plaques and tangles, and explain the biochemical, neuropathological and cognitive changes observed with disease progression. Since sex hormones control when and how neurons proliferate and differentiate, the endocrine dyscrasia that accompanies menopause and andropause is a key signaling event that impacts neurogenesis and the acquisition, processing, storage and recall of memories. Here we review the biochemical, epidemiological and clinical evidence that alterations in endocrine signaling with menopause and andropause drive the aberrant re-entry of post-mitotic neurons into an abortive cell cycle with neurite retraction that leads to neuron dysfunction and death. When the reproductive axis is in balance, luteinizing hormone (LH), and its fetal homolog, human chorionic gonadotropin (hCG), promote pluripotent human and totipotent murine embryonic stem cell and neuron proliferation. However, strong evidence supports menopausal/andropausal elevations in the ratio of LH:sex steroids as driving aberrant mitotic events mediated by the upregulation of tumor necrosis factor, amyloid-β precursor protein processing towards the production of mitogenic Aβ, and the activation of Cdk5, a key regulator of cell cycle progression and tau phosphorylation (a cardinal feature of both neurogenesis and neurodegeneration). Cognitive studies also demonstrate the negative consequences of a high LH:sex steroid ratio on human cognitive performance. Prospective epidemiological and clinical evidence in humans supports lowering the ratio of circulating gonadotropins-GnRH to sex steroids in reducing the incidence of AD and halting cognitive decline. Together, these data support endocrine dyscrasia and the subsequent loss of cell cycle control as an important etiological event in the development of neurodegenerative diseases including AD, stroke and Parkinson’s disease.

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Developmental and aging changes in the expression patterns of beta-amyloid in the brains of normal and down syndrome cases

Cited by 29 publications

References 16 publications

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

Gonadotropins and Progestogens: Obligatory Developmental Functions during Early Embryogenesis and their Role in Adult Neurogenesis, Neuroregeneration and Neurodegeneration

The endocrine dyscrasia that accompanies menopause and andropause induces aberrant cell cycle signaling that triggers re-entry of post-mitotic neurons into the cell cycle, neurodysfunction, neurodegeneration and cognitive disease

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