Alzheimer's disease: the two-hit hypothesis

Zhu, Xiongwei; Raina, Arun K.; Perry, George; Smith, Mark A.

doi:10.1016/s1474-4422(04)00707-0

Cited by 398 publications

(296 citation statements)

References 128 publications

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“…These reports strongly suggest that human LOAD development can be aided by prolonged mitosis, which the Sgo1 −/+ model recapitulates. Indeed, in human LOAD, models incorporating the critical role of mitotic cells have been proposed, such as a “simple linear model” that states that human AD pathology develops from mitotic cycle‐reentering neurons that later die (Herrup, 2010), and the “two‐hit model” of human LOAD (Zhu, Lee, Perry, & Smith, 2007; Zhu, Raina, Perry, & Smith, 2004) that purports that LOAD development occurs with (a) oxidative stress and (b) mitotic reentry. Although the direct trigger for mitotic cycle reentry in Sgo1 −/+ model mice remains unclear, studies on roles of cell cycle regulators, such as Cdk5 (Zhang et al., 2008), and on effects of genes identified through RNA‐seq in this study on the cell cycle, are warranted.…”

Section: Discussionmentioning

confidence: 99%

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Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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SummarySpontaneous late‐onset Alzheimer's disease (LOAD) accounts for more than 95% of all human AD. As mice do not normally develop AD and as understanding on molecular processes leading to spontaneous LOAD has been insufficient to successfully model LOAD in mouse, no mouse model for LOAD has been available. Existing mouse AD models are all early‐onset AD (EOAD) models that rely on forcible expression of AD‐associated protein(s), which may not recapitulate prerequisites for spontaneous LOAD. This limitation in AD modeling may contribute to the high failure rate of AD drugs in clinical trials. In this study, we hypothesized that genomic instability facilitates development of LOAD and tested two genomic instability mice models in the brain pathology at the old age. Shugoshin‐1 (Sgo1) haploinsufficient (∓) mice, a model of chromosome instability (CIN) with chromosomal and centrosomal cohesinopathy, spontaneously exhibited a major feature of AD pathology; amyloid beta accumulation that colocalized with phosphorylated Tau, beta‐secretase 1 (BACE), and mitotic marker phospho‐Histone H3 (p‐H3) in the brain. Another CIN model, spindle checkpoint‐defective BubR1−/+ haploinsufficient mice, did not exhibit the pathology at the same age, suggesting the prolonged mitosis‐origin of the AD pathology. RNA‐seq identified ten differentially expressed genes, among which seven genes have indicated association with AD pathology or neuronal functions (e.g., ARC, EBF3). Thus, the model represents a novel model that recapitulates spontaneous LOAD pathology in mouse. The Sgo1−/+ mouse may serve as a novel tool for investigating mechanisms of spontaneous progression of LOAD pathology, for early diagnosis markers, and for drug development.

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Section: Discussionmentioning

confidence: 99%

“…We speculate that functional equivalent of Sgo1 mutation can also create LOAD model. Indeed, functional equivalent of Sgo1 mutation, such as accumulation of aneuploid cells (Bajic et al., 2015; Potter, 1991) or increase in cells reentering mitotic cycle, does occur in human LOAD (Herrup, 2010; Zhu et al., 2004, 2007). …”

Section: Discussionmentioning

confidence: 99%

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

et al. 2018

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“…Tau hyperphosphorylation in SAMP8 is mediated by AD-related mechanisms, such as increases in Cdk5 expression [55]. Moreover, treatments such as melatonin [57,58] and lithium chloride [59] that reduce Cdk5 and GSK3β activation and activation of the cdk5/p35 pathway at its cleavage to cdk5/p25, which are all key players in AD-related hyperphosphorylation of tau during aging and neurodegenerative diseases [4,60], lead to a reduction in tau hyperphosphorylation when administered to SAMP8.…”

Section: Histopathological Similarities In Samp8 and Admentioning

confidence: 99%

“…If aging-associated processes result from oxidative stress, then some of the most prevalent neurodegenerative diseases associated mainly with the deleterious effects of time on cellular mechanisms can also be linked to an imbalance in the homeostatic mechanism controlling oxidative processes in the whole organism and particularly in brain [3]. The main neurodegenerative diseases are Alzheimer's (AD), Parkinson's, Huntington's, or amyotrophic lateral sclerosis [4,5]. Of these, AD is the most prevalent.…”

Section: Introduction To the Model: The Origin Of Senescence-acceleramentioning

confidence: 99%

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Pallàs

2012

ISRN Cell Biology

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The causes of aging remain unknown, but they are probably intimately linked to a multifactorial process that affects cell networks to varying degrees. Although a growing number of aging and Alzheimer's disease (AD) animal models are available, a more comprehensive and physiological mouse model is required. In this context, the senescence-accelerated mouse prone 8 (SAMP8) has a number of advantages, since its rapid physiological senescence means that it has about half the normal lifespan of a rodent. In addition, according to data gathered over the last five years, some of its behavioral traits and histopathology resemble AD human dementia. SAMP8 has remarkable pathological similarities to AD and may prove to be an excellent model for acquiring more in-depth knowledge of the age-related neurodegenerative processes behind brain senescence and AD in particular. We review these facts and particularly the data on parameters related to neurodegeneration. SAMP8 also shows signs of aging in the immune, vascular, and metabolic systems, among others.

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“…Impaired energy metabolism and hypoperfusion of the brain are related to oxidative stress and aberrant mitogenic changes in AD pathogenesis. Zhu et al (2004) addressed the possibility that although either latter mechanism can independently serve as AD initiator, both are necessary to propagate disease pathogenesis. This was called the ''two-hit hypotheses.…”

Section: Reflection Points For Future Researchmentioning

confidence: 99%

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

Polidori

Schulz

2014

Genes Nutr

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There is an impressing body of evidence supporting the beneficial role of balanced nutrition in lowering the risk of dementia and its commonest form, Alzheimer's disease. Nevertheless, and despite worldwide dementia epidemic, there is much unfounded skepticism and lack of information among physicians. As a result, the diagnosis of cognitive impairment occurs still far too late, at best symptomatic drugs keep being prescribed and patients and caregivers are left with little concrete support in the hands of the natural history of the disease. This review summarizes knowledge about the impact of nutrition as part of a healthy lifestyle and of micronutrients in particular on delaying and avoiding dementia onset.Why do we need to care about dementia Dementia is the most prevalent neurodegenerative disorder, and it is characterized by progression, multiple etiology, complex symptomatology including that related to a disturbance of cognitive performance and absence of a cure. During the course of the disease, the cognitive symptoms of dementia persist and steadily worsen and behavioral disturbances appear and progress and as a result intellectual and social abilities are affected enough to obstacle the performance of activities of daily living. According to dementia definition, a diagnosis of dementia can be done when the impairment of more cognitive domains lasts long enough and is associated with behavioral disturbances both affecting activities of daily living. Dementia is indeed associated with disability and a high grade of dependence on caregivers-usually family members. This condition of disability and dependence brings along an enormous social and economic burden which is linked to the epidemics of dementia and its commonest, untreatable form, Alzheimer's disease (AD). The major risk factor for dementia and AD is advanced age, and therefore, the societal impact of AD is increasing according to aging demographics (http:// ec.europa.eu/health/reports/european). Life expectancy at birth in the EU increased from 72 years in 1980 to 78 years in 2007. The population of industrialized countries progressed from a mean life expectancy of 35 years at the beginning of the last century, to currently over 80 years of age. People aged 65 years or older are expected to double between 1995 and 2050 to reach 135 million in the EU, with very old people, aged 80 years and older, being projected to grow as much as eight to ten times on the global scale by 2050. This will strongly impact the already challenging number of ten million AD cases in the EU. As a cure against dementia has not been found yet, health care professionals all over the world are predicted to face the diagnostic, therapeutic and socioeconomical challenges of over 115 million people with dementia by 2050 (Prince et al. 2013). This perspective might be even underestimated, particularly due to inadequate diagnosis, lack of awareness and low education. The dramatic loss of synapses and cholinergic neurons, accumulation of extracellular b amyloid (Ab) plaqu...

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Alzheimer's disease: the two-hit hypothesis

Cited by 398 publications

References 128 publications

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Spontaneous development of Alzheimer's disease‐associated brain pathology in a Shugoshin‐1 mouse cohesinopathy model

Senescence-Accelerated Mice P8: A Tool to Study Brain Aging and Alzheimer's Disease in a Mouse Model

Nutritional contributions to dementia prevention: main issues on antioxidant micronutrients

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