Altered neurogenesis in mouse models of Alzheimer disease

Wirths, Oliver

doi:10.1080/23262133.2017.1327002

Cited by 41 publications

(35 citation statements)

References 53 publications

(56 reference statements)

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“…Adult hippocampal neurogenesis consists of three main stages: proliferation, differentiation, and survival (Dard et al, 2019). Controversy exists in the literature as to whether hippocampal neurogenesis is increased or decreased in mouse models of AD (Rodríguez et al, 2008;Demars et al, 2010;Hamilton et al, 2010;Krezymon et al, 2013; for reviews see Wirths, 2017;Dard et al, 2019). However, altered neurogenesis must still provide some cognitive benefit as conditional ablation of adult neurogenesis in APP Swe /PS1 E9 mice worsened behavioral performance in contextual conditioning and pattern separation tasks (Hollands et al, 2017).…”

Section: Neurogenesismentioning

confidence: 99%

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

2020

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Alzheimer's disease (AD) is a progressive neurodegenerative disease that is the most common cause of dementia. Symptoms of AD include memory loss, disorientation, mood and behavior changes, confusion, unfounded suspicions, and eventually, difficulty speaking, swallowing, and walking. These symptoms are caused by neuronal degeneration and cell loss that begins in the hippocampus, and later in disease progression spreading to the rest of the brain. While there are some medications that alleviate initial symptoms, there are currently no treatments that stop disease progression. Hippocampal deficits in amyloid-β-related rodent models of AD have revealed synaptic, behavioral and circuit-level defects. These changes in synaptic function, plasticity, neuronal excitability, brain connectivity, and excitation/inhibition imbalance all have profound effects on circuit function, which in turn could exacerbate disease progression. Despite, the wealth of studies on AD pathology we don't yet have a complete understanding of hippocampal deficits in AD. With the increasing development of in vivo recording techniques in awake and freely moving animals, future studies will extend our current knowledge of the mechanisms underpinning how hippocampal function is altered in AD, and aid in progression of treatment strategies that prevent and/or delay AD symptoms.

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Section: Neurogenesismentioning

confidence: 99%

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

2020

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“…Much work on postmortem AD brains, the brains of numerous AD-relevant animal models, and cultured cells has been directed toward understanding how amyloid, primarily amyloid-␤ 1-42 (A␤ 42 ), is deposited in the brain within neurons and amyloid plaques throughout AD pathogenesis [3,7,8]. Although plaque formation in human AD brains is still generally considered an extracellular event, intracellular A␤ 42 deposition has been reported as an early pathological marker in AD brains, in the brains of AD-relevant transgenic animal models, and in various types of cultured neurons and neuron-like cells [9][10][11][12][13][14][15][16][17][18]. A␤ 42 has been shown to bind with high affinity to the alpha7 subtype of the nicotinic acetylcholine receptor (␣7nAChR), which is abundantly present on the surfaces of cholinergic and cholinoceptive neurons (especially on cortical pyramidal cells) [9,12,19,20].…”

Section: Introductionmentioning

confidence: 99%

Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer’s Disease Pathogenesis

Goldwaser

Acharya

et al. 2020

JAD

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Blood-brain barrier (BBB) permeability is a recognized early feature of Alzheimer's disease (AD). In the present study, we examined consequences of increased BBB permeability on the development of AD-related pathology by tracking selected leaked plasma components and their interactions with neurons in vivo and in vitro. Histological sections of cortical regions of postmortem AD brains were immunostained to determine the distribution of amyloid-␤ 1-42 (A␤ 42), cathepsin D, IgG, GluR2/3, and alpha7 nicotinic acetylcholine receptor (␣7nAChR). Results revealed that chronic IgG binding to pyramidal neurons coincided with internalization of A␤ 42, IgG, GluR2/3, and ␣7nAChR as well as lysosomal compartment expansion in these cells in regions of AD pathology. To test possible mechanistic interrelationships of these phenomena, we exposed differentiated SH-SY5Y neuroblastoma cells to exogenous, soluble A␤ 42 peptide and serum from AD and control subjects. The rate and extent of A␤ 42 internalization in these cells was enhanced by serum containing neuron-binding IgG autoantibodies. This was confirmed by treating cells with individual antibodies specific for ␣7nAChR, purified IgG from AD or non-AD sera, and sera devoid of IgG, in the presence of 100 nM A␤ 42. Initial co-localization of IgG, ␣7nAChR, and A␤ 42 was temporally and spatially linked to early endosomes (Rab11) and later to lysosomes (LAMP-1). A␤ 42 internalization was attenuated by treatment with monovalent F(ab) antibody fragments generated from purified IgG from AD serum and then

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“…The existing AD mouse models are EOAD models that rely on expression(s) of modified EOAD-associated protein(s), including APP, TAU, presenilin, and ApoE [17][18][19][20][21]. EOAD models successfully replicate extracellular amyloid plaques short-term (time for plaque onset: 9-12 months for TG2576, 6 months for 3xTG, 2 months for APP 751SL / PS1KI) [22]. However, since the EOAD models are overexpression models, it is questionable whether they recapitulate prerequisites for spontaneous LOAD that may occur with age in humans.…”

Section: Introductionmentioning

confidence: 99%

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

et al. 2018

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From early-onset Alzheimer's disease (EOAD) studies, the amyloid-beta hypothesis emerged as the foremost theory of the pathological causes of AD. However, how amyloid-beta accumulation is triggered and progresses toward senile plaques in spontaneous late-onset Alzheimer's disease (LOAD) in humans remains unanswered. Various LOAD facilitators have been proposed, and LOAD is currently considered a complex disease with multiple causes. Mice do not normally develop LOAD. Possibly due to the multiple causes, proposed LOAD facilitators have not been able to replicate spontaneous LOAD in mice, representing a disease modeling issue. Recently, we reported spontaneous late-onset development of amyloid-beta accumulation in brains of Shugoshin 1 (Sgo1) haploinsufficient mice, a cohesinopathy-mediated chromosome instability model. The result for the first time expands disease relevance of mitosis studies to a major disease other than cancers. Reverse-engineering of the model would shed light on the process of late-onset amyloid-beta accumulation in the brain and spontaneous LOAD development, and contribute to development of interventions for LOAD. This review will discuss the Sgo1 model, our current "three-hit hypothesis" regarding LOAD development with an emphasis on critical role of prolonged mitosis in amyloid-beta accumulation, and implications for human LOAD intervention and treatment. Abbreviations: Alzheimer's disease (AD); Late-onset Alzheimer's disease (LOAD); Early-onset Alzheimer's disease (EOAD); Shugoshin-1 (Sgo1); Chromosome Instability (CIN); apolipoprotein (Apoe); Central nervous system (CNS); Amyloid precursor protein (APP); N-methyl-d-aspartate (NMDA); Hazard ratio (HR); Cyclin-dependent kinase (CDK); Chronic Atrial Intestinal Dysrhythmia (CAID); beta-secretase 1 (BACE); phosphor-Histone H3 (p-H3); Research and development (R&D); Non-steroidal anti-inflammatory drugs (NSAIDs); Brain blood barrier (BBB).

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Altered neurogenesis in mouse models of Alzheimer disease

Cited by 41 publications

References 53 publications

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

Hippocampal Deficits in Amyloid-β-Related Rodent Models of Alzheimer’s Disease

Evidence that Brain-Reactive Autoantibodies Contribute to Chronic Neuronal Internalization of Exogenous Amyloid-β1-42 and Key Cell Surface Proteins During Alzheimer’s Disease Pathogenesis

Critical role of mitosis in spontaneous late-onset Alzheimer’s disease; from a Shugoshin 1 cohesinopathy mouse model

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