Animal models of amyloid‐β‐related pathologies in Alzheimer’s disease

Philipson, Ola; Lord, Anna; Gumucio, Astrid; O’Callaghan, Paul; Lannfelt, Lars; Nilsson, Lars

doi:10.1111/j.1742-4658.2010.07564.x

Cited by 93 publications

(91 citation statements)

References 164 publications

(191 reference statements)

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“…Familial AD is linked to inherited mutations in AD-related genes and represents a small percentage of AD cases, whereas sporadic AD represents the vast majority of cases and is not inherited. Results from transgenic mice bearing mutations in APP, PSEN1/2, and TAU show synaptic dysfunction in early stages of AD, before overt neurodegeneration (2,3). More recent studies have demonstrated a critical role for soluble Aβ oligomers as an early trigger for AD, as well as associations with memory and neural plasticity loss (4)(5)(6)(7)(8).…”

mentioning

confidence: 99%

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Ardiles

Tapia-Rojas

Mandal

et al. 2012

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

122

107

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Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with progressive memory loss, severe dementia, and hallmark neuropathological markers, such as deposition of amyloid-β (Aβ) peptides in senile plaques and accumulation of hyperphosphorylated tau proteins in neurofibrillary tangles. Recent evidence obtained from transgenic mouse models suggests that soluble, nonfibrillar Aβ oligomers may induce synaptic failure early in AD. Despite their undoubted value, these transgenic models rely on genetic manipulations that represent the inherited and familial, but not the most abundant, sporadic form of AD. A nontransgenic animal model that still develops hallmarks of AD would be an important step toward understanding how sporadic AD is initiated. Here we show that starting between 12 and 36 mo of age, the rodent Octodon degus naturally develops neuropathological signs of AD, such as accumulation of Aβ oligomers and phosphorylated tau proteins. Moreover, age-related changes in Aβ oligomers and tau phosphorylation levels are correlated with decreases in spatial and object recognition memory, postsynaptic function, and synaptic plasticity. These findings validate O. degus as a suitable natural model for studying how sporadic AD may be initiated. memory dysfunction | neural plasticity | aging | T-maze | hippocampus A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by the accumulation of abnormally processed proteins in neurofibrillary tangles (NFTs) and senile plaques (1). These lesions are present in both familial and sporadic forms of AD. Familial AD is linked to inherited mutations in AD-related genes and represents a small percentage of AD cases, whereas sporadic AD represents the vast majority of cases and is not inherited. Results from transgenic mice bearing mutations in APP, PSEN1/2, and TAU show synaptic dysfunction in early stages of AD, before overt neurodegeneration (2, 3). More recent studies have demonstrated a critical role for soluble Aβ oligomers as an early trigger for AD, as well as associations with memory and neural plasticity loss (4-8).Although transgenic mice have been extremely useful in elucidating the pathological mechanisms of AD, they have some substantial limitations. Examples include the absence of tau mutations linked to AD except for a triple transgenic mouse 3xTg-AD, bearing mutations for APP, PSEN1/2, and TAU (9); inability to develop the whole spectrum of the disease; overexpression of transgenes into a nonphysiological scenario; and the fact that the manipulated genes represent only familial, not sporadic forms of AD (10, 11). It would be highly desirable to have a nontransgenic model of AD to complement the existing models. Several species naturally develop features of AD with age; however, the usefulness of these species is limited, because none exhibits the full spectrum of AD-related alterations (12-14). For example, the Aβ peptide sequences of Cavia porcellus (guinea pig) and Microcebus murinus are similar to that of huma...

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confidence: 99%

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Ardiles

Tapia-Rojas

Mandal

et al. 2012

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

122

107

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“…However, partial reproduction of AD neuropathology and cognitive deficits has been achieved with various approaches (20,21). Mouse models have been established that express identified human mutations that give rise to these pathological hallmarks of AD (19,(21)(22)(23). Despite their undoubted value, the transgenic Q.L.…”

Section: Discussionmentioning

confidence: 99%

APP/PS1 Transgenic Mice Treated with Aluminum: An Update of Alzheimer's Disease Model

Zhang

Jia

Jiao

et al. 2012

Int J Immunopathol Pharmacol

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There is still no animal model available that can mimic all the cognitive, behavioral, biochemical, and histopathological abnormalities observed in patients with Alzheimer's disease (AD). We undertook to consider the interaction between genetic factors, including amyloid precursor protein (APP) and presenllin-I (PSI), and environmental factors, such as Aluminum (AI) in determining susceptibility outcomes when studying the pathogenesis of AD. In this article, we provide an AD model in APP/ PSI transgenic mice triggered by AI. The animal model was established via intracerebral ventricular microinjection of aluminum chloride once a day for 5 days in APP/PSI transgenic mice. Twenty wild type (WT) mice and 20 APP/PSI transgenic (TG) mice were separately divided into 2 groups (control and Al group), and a stainless steel injector with stopper was used for microinjection into the left-lateral cerebral ventricle of each mouse. The Morris water maze task was used to evaluate behavioral function of learning and memory ability on the 20th day after the last injection. This AD model's brain was analyzed by: (1) amyloid p immunohistochemical staining; (2) Tunnel staining; (3) apoptotic rates; (l:a) caspase-3 gene expression. Here, decrease of cognitive ability and neural cells loss were shown in APP/ PSI transgenic mice exposed to AI, which were more extensive than those in APP/PSI TG alone and WT mice exposed to Al alone. These findings indicate that there is a close relationship between overexpression of APP and PSI genes and Al overload. It is also suggested that APP/PSI TG mice exposed to Al have potential value for improving AD models.Development of adequate animal models mimicking all stages of Alzheimer's disease (AD) progression and merging convergent pathways of pathogenesis represents a need for research on AD. Amyloid plaques and neurofibrillary tangles are the two most widely recognized hallmarks of AD, the molecular events pertaining to their formation have been under intensive study for over a decade. A number of AD models rely on information gathered from inherited familial forms including various human pedigrees of gene mutations in amyloid precursor protein (APP), presenilin-I (PSI) and presenilin-2 (PS2) (l, 2). Despite their undoubted value, transgenic AD mice show a number ofpitfalls (3). That is, they fail to model the progressive stages of the disease or to show significant neuron loss.Environmental toxins as risk factors may contribute to the development ofAD (3). Aluminum

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“…4 Inflammatory factors have been further implicated in cognitive impairment and dementia using mouse models. 5 These include transgenic animals in which chemoattractant proteins or receptors such as Ccl2 or Ccr2 have been abolished. 5 These genes, associated with the migration of phagocytic and inflammatory macrophages, have been associated with Alzheimer pathology and peripheral atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

“…5 These include transgenic animals in which chemoattractant proteins or receptors such as Ccl2 or Ccr2 have been abolished. 5 These genes, associated with the migration of phagocytic and inflammatory macrophages, have been associated with Alzheimer pathology and peripheral atherosclerosis. [5][6][7] Ccr2-deficient mice show early accumulation of b-amyloid, with premature mortality.…”

Section: Introductionmentioning

confidence: 99%

“…5 These genes, associated with the migration of phagocytic and inflammatory macrophages, have been associated with Alzheimer pathology and peripheral atherosclerosis. [5][6][7] Ccr2-deficient mice show early accumulation of b-amyloid, with premature mortality. 7 Blood-borne systemic factors, including CCR2 and CCL11, were also recently implicated in the negative regulation of neurogenesis and cognitive function in rodent studies.…”

Section: Introductionmentioning

confidence: 99%

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LeukocyteCCR2Expression Is Associated with Mini-Mental State Examination Score in Older Adults

Harries

Bradley-Smith

Llewellyn

et al. 2012

Rejuvenation Research

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Introduction: Circulating inflammatory markers may play an important role in cognitive impairment at older ages. Mice deficient for the chemokine (C-C motif) receptor 2 (CCR2) develop an accelerated Alzheimer-like pathology. CCR2 is also important in neurogenesis. To identify human gene transcripts most closely associated with Mini-Mental State Examination (MMSE) scores, we undertook a genome-wide and inflammation specific transcriptome screen in circulating leukocytes from a population-based sample. Methods: We measured in vivo transcript levels by microarray analysis in 691 subjects (mean age 72.6 years) in the InCHIANTI study (Invecchiare in Chianti, aging in the Chianti area). We assessed expression associations with MMSE performance at RNA collection and prior 9-year change in MMSE score in linear regression models. Results: In genome-wide analysis, raised CCR2 expression was cross-sectionally the most strongly associated transcript with lower MMSE score (beta = -0.16, p = 5.1 · 10 -6 , false discovery rate (FDR; q = 0.077). Amongst inflammatory transcripts, only CCR2 expression was associated with both MMSE score and accelerated decline in score over the preceding 9 years (beta = -0.16, p = 5.1 · 10 -6 , q = 0.003; and beta = -0.13, p = 5.5 · 10 -5 , q = 0.03, respectively). CCR2 expression was also positively associated with apolipoprotein E (ApoE) e4 Alzheimer disease risk haplotype. Conclusions: We show for the first time that CCR2 expression is associated with lower MMSE scores in an older human population. Laboratory models of Ccr2-mediated b-amyloid removal and regulation of neurogenesis affecting cognitive function may be applicable in humans. CCR2-mediated pathways may provide a possible focus for intervention to potentiate protective reactions to Alzheimer pathology in older people, including for people with an adverse ApoE haplotype.

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Animal models of amyloid‐β‐related pathologies in Alzheimer’s disease

Cited by 93 publications

References 164 publications

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

Postsynaptic dysfunction is associated with spatial and object recognition memory loss in a natural model of Alzheimer’s disease

APP/PS1 Transgenic Mice Treated with Aluminum: An Update of Alzheimer's Disease Model

LeukocyteCCR2Expression Is Associated with Mini-Mental State Examination Score in Older Adults

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