Neuron Loss in Transgenic Mouse Models of Alzheimer's Disease

Division of Molecular Psychiatry and Alzheimer Ph.D. Graduate School, Department of Psychiatry, University of Goettingen, von-Siebold-Str. 5, 37075 Goettingen, Germany.
International Journal of Alzheimer's Disease 08/2010; 2010. DOI: 10.4061/2010/723782
Source: PubMed


Since their initial generation in the mid 1990s, transgenic mouse models of Alzheimers's disease (AD) have been proven to be valuable model systems which are indispensable for modern AD research. Whereas most of these models are characterized by extensive amyloid plaque pathology, inflammatory changes and often behavioral deficits, modeling of neuron loss was much less successful. The present paper discusses the current achievements of modeling neuron loss in transgenic mouse models based on APP/Aβ and Tau overexpression and provides an overview of currently available AD mouse models showing these pathological alterations.

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    • "e l s e v ie r . c o m / l o c a t e / n e u a g i n g mutant human tau, (Oddo et al., 2003)) are also expressed and neurodegeneration seldom occurs (Wirths and Bayer, 2010). Strikingly , despite successful pharmacologic amelioration of AD pathology and attenuation of cognitive decline over 300 times in such animal models, none of these promising preclinical findings have translated into effective and safe human therapies (Zahs and Ashe, 2010). "
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    ABSTRACT: Tau protein is primarily expressed in neuronal axons and modulates microtubule stability. Tau phosphorylation, aggregation, and subcellular mislocalization coincide with neurodegeneration in numerous diseases, including Alzheimer's disease (AD). During AD pathogenesis, tau misprocessing accompanies Aß accumulation; however, AD animal models, despite elevated Aß, fail to develop tauopathy. To assess whether lack of tau pathology is linked to short life span common to most AD models, we examined tau processing in extraordinarily long-lived, mouse-sized naked mole-rats (NMRs; approximately 32 years), which express appreciable levels of Aß throughout life. We found that NMRs, like other mammals, display highest tau phosphorylation during brain development. Although tau phosphorylation decreases with aging, unexpectedly adult NMRs have higher levels than transgenic mice overexpressing mutant human tau. However, in sharp contrast with the somatodendritic accumulation of misprocessed tau in the transgenic mice, NMRs maintain axonal tau localization. Intriguingly, the adult NMR tau protein is 88 kDa, much larger than 45-68 kDa tau expressed in other mammals. We propose that this 88 kDa tau protein may offer exceptional microtubule stability and neuroprotection against lifelong, elevated Aß. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.12.004 · 5.01 Impact Factor
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    • "While β-amyloid plaques and neurofibrillary tangles are accepted as the pathological hallmarks of AD, it is still unclear how this pathology causes impairment of cognition. Progressive neuronal loss as described for particular regions of the AD brain in humans (West et al., 1994) and in AD animal models (Wirths and Bayer, 2010) is usually taken responsible for the mental derangement at late stages of the disease. "
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    ABSTRACT: Disruption of neuronal networks in the Alzheimer-afflicted brain is increasingly recognized as a key correlate of cognitive and memory decline in Alzheimer patients. We hypothesized that functional synaptic disconnections within cortical columnar microcircuits by pathological β- amyloid accumulation, rather than cell death, initially causes the cognitive impairments. During development of cortical β-amyloidosis with still few plaques in the transgenic 5xFAD mouse model single cell resolution mapping of neuronal thallium uptake revealed that electrical activity of pyramidal cells breaks down throughout infragranular cortical layer V long before cell death occurs. Treatment of 5xFAD mice with the glutaminyl cyclase inhibitor, PQ 529, partially prevented the decline of pyramidal cell activity, indicating pyroglutamate-modified forms, potentially mixed oligomers of Aβ, are contributing to neuronal impairment. Laminar investigation of cortical circuit dysfunction with current source density analysis identified an early loss of excitatory synaptic input in infragranular layers, linked to pathological recurrent activations in supragranular layers. This specific disruption of normal cross-laminar cortical processing coincided with a decline of contextual fear learning.
    Neurobiology of Disease 11/2013; 63. DOI:10.1016/j.nbd.2013.11.014 · 5.08 Impact Factor
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    • "In addition, knock-in strategies to induce genetic mutations in APP or PS1 in rodents have been proven not to be sufficient to evoke AD-like phenotypes [8,9]. The development of certain features of the disease in animal models depends on transgene overexpression [10,11] and combinations of mutations [12-14]. Only very strong promoters and the presence of multiple mutations in mice, a combination never occuring in AD patients, triggers most of the neuropathological and behavioral phenotypes observed in humans, albeit in very young animals [15]. "
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    ABSTRACT: For the last 20 years, the "amyloid cascade hypothesis" has dominated research aimed at understanding, preventing, and curing Alzheimer's disease (AD). During that time researchers have acquired an enormous amount of data and have been successful, more than 300 times, in curing the disease in animal model systems by treatments aimed at clearing amyloid deposits. However, to date similar strategies have not been successful in human AD patients. Hence, before rushing into further clinical trials with compounds that aim at lowering amyloid-beta (Aβ) levels in increasingly younger people, it would be of highest priority to re-assess the initial assumption that accumulation of Aβ in the brain is the primary pathological event driving AD. Here we question this assumption by highlighting experimental evidence in support of the alternative hypothesis suggesting that APP and Aβ are part of a neuronal stress/injury system, which is up-regulated to counteract inflammation/oxidative stress-associated neurodegeneration that could be triggered by a brain injury, chronic infections, or a systemic disease. In AD, this protective program may be overridden by genetic and other risk factors, or its maintenance may become dysregulated during aging. Here, we provide a hypothetical example of a hypothesis-driven correlation between car accidents and airbag release in analogy to the evolution of the amyloid focus and as a way to offer a potential explanation for the failure of the AD field to translate the success of amyloid-related therapeutic strategies in experimental models to the clinic.
    09/2013; 1(1):62. DOI:10.1186/2051-5960-1-62
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