Animal Models of Alzheimer Disease

LaFerla, Frank M.; Green, Kim N.

doi:10.1101/cshperspect.a006320

Cited by 362 publications

(230 citation statements)

References 89 publications

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“…refs. 2,3). While a myriad of experimental therapeutic interventions has been reported that describe an ambiguous situation with regard to an amelioration of these pathological alterations, literature on non-pharmacological treatment and prevention by increased physical activity is more consistent.…”

Section: Introductionmentioning

confidence: 99%

Altered neurogenesis in mouse models of Alzheimer disease

Wirths

2017

Neurogenesis

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Amyloid-b (Ab) peptides, as well as a variety of other protein fragments, are derived from proteolytical cleavage of the amyloid precursor protein (APP) and have been demonstrated to play a key role in the pathological changes underlying Alzheimer disease (AD). In AD mouse models, altered neurogenesis has been repeatedly reported to be associated with further AD-typical pathological hallmarks such as extracellular plaque deposition, behavioral deficits or neuroinflammation. While a toxic role of Ab in neurodegeneration and impaired neuronal progenitor proliferation is likely and well-accepted, recent findings also suggest an important influence of APP-derived proteolitical fragments like the APP intracellular domain (AICD), as well as of APP itself.

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Section: Introductionmentioning

confidence: 99%

Altered neurogenesis in mouse models of Alzheimer disease

Wirths

2017

Neurogenesis

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“…Nonetheless, more than a century after the original definition of the disease, the identification of the fundamental cell biological processes that cause AD remains a major challenge. Major defining features of AD brain pathology, as elucidated by molecular and genetic studies in humans and mice, are as follows: the proteolytic processing of the amyloid precursor protein (APP) by the successive action of β-and γ-secretases to generate the toxic Aβ peptides, the accumulation of extracellular aggregates of Aβ, synapse dysfunction, and death of specific subpopulations of neurons (1)(2)(3)(4)(5)(6). However, although mutations that result in enhanced APP expression and/or altered processing of APP into Aβ peptides drive the development of a subset of early onset familial forms of AD, the causes of the vastly more common late-onset AD are much less well understood.…”

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confidence: 99%

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Gowrishankar

Yuan

et al. 2015

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

328

326

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Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

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“…The similarity of drug transporters allows oral drug absorption, but not oral bioavailability, to be predicted with great success in the rat model [69]. The rat shares the same expression and distribution of drug transporters in the intestine with the exception of P-glycoprotein, Table 2: Some animal species have been ingrained as models for specific diseases and areas of study [4,8,10,64,66,10,[104][105][106][107][108][109][110][111][112][113][114][115]. multi-drug resistance protein 3, and glucose transporter 1 and 3 [69].…”

Section: Choosing a Model Animalmentioning

confidence: 99%

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

Brake¹,

Gumireddy²,

Tiwari³

et al. 2017

Pharm Anal Acta

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Drug discovery and development involves a complex iterative process of new molecules synthesis, formulations, and in vitro analysis, followed by biochemical and cellular assays, with final validation in animal models, and ultimately in humans. The purpose of this article is to present a concise overview of the rationale and challenges for performing in vivo studies, the types of animal models, and modern in vivo research techniques for oral drug delivery.

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Animal Models of Alzheimer Disease

Cited by 362 publications

References 89 publications

Altered neurogenesis in mouse models of Alzheimer disease

Altered neurogenesis in mouse models of Alzheimer disease

Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

In vivo Studies for Drug Development via Oral Delivery: Challenges, Animal Models and Techniques

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