Rodent models for Alzheimer’s disease drug discovery

Puzzo, Daniela; Gulisano, Walter; Palmeri, Agostino; Arancio, Ottavio

doi:10.1517/17460441.2015.1041913

Cited by 182 publications

(131 citation statements)

References 88 publications

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“…However, data from APP mutant models are mixed [180][181] [182]: Some cases show normal behavior despite high amyloid levels [183], while impairments resembling AD features can be induced by other features such as metabolic deficiencies [184].…”

Section: Challenging the Amyloid Hypothesismentioning

confidence: 99%

Alzheimer’s disease due to loss of function: A new synthesis of the available data

Kepp

2016

Progress in Neurobiology

120

107

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Alzheimer's Disease (AD) is a highly complex disease involving a broad range of clinical, cellular, and biochemical manifestations that are currently not understood in combination. This has led to many views of AD, e.g. the amyloid, tau, presenilin, oxidative stress, and metal hypotheses. The amyloid hypothesis has dominated the field with its assumption that buildup of pathogenic β-amyloid (Aβ) peptide causes disease. This paradigm has been criticized, yet most data suggest that Aβ plays a key role in the disease. Here, a new loss-of-function hypothesis is synthesized that accounts for the anomalies of the amyloid hypothesis, e.g. the curious pathogenicity of the Aβ42/Aβ40 ratio, the loss of Aβ caused by presenilin mutation, the mixed phenotypes of APP mutations, the poor clinical-biochemical correlations for genetic variant carriers, and the failure of Aβ reducing drugs. The amyloid-loss view accounts for recent findings on the structure and chemical features of Aβ variants and their coupling to human patient data. The lost normal function of APP/Aβ is argued to be metal transport across neuronal membranes, a view with no apparent anomalies and substantially more explanatory power than the gain-of-function amyloid hypothesis. In the loss-of-function scenario, the central event of Aβ aggregation is interpreted as a loss of soluble, functional monomer Aβ rather than toxic overload of oligomers. Accordingly, new research models and treatment strategies should focus on remediation of the functional amyloid balance, rather than strict containment of Aβ, which, for reasons rationalized in this review, has failed clinically.

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Section: Challenging the Amyloid Hypothesismentioning

confidence: 99%

Alzheimer’s disease due to loss of function: A new synthesis of the available data

Kepp

2016

Progress in Neurobiology

120

107

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“…The protective A2T mutation [125] has been widely used as a showcase of the amyloid hypothesis [101], and its lower produced A levels fit well to quantitative gain of function as the protective alternative to the Swedish mutation and A2V [126]. The Swedish mutation produces very high A levels and is the most used transgenic mouse model in AD research [127], yet it only models the type of overproduction of A consistent with the now obsolete "cascade" hypothesis.…”

Section: Ten Challenges Of the Amyloid Hypothesismentioning

confidence: 99%

“…To move forward on these various challenges, we must i) solve the data heterogeneity issue of peptide preparations and measurements; ii) actively use available human patient data 14 that tell us about the real aging human disease, considering the challenges of mouse models [127]; iii) unite sporadic and familial disease forms as we move beyond the FADmutation-based research models and towards chemical-aging models that account for the aging phenotype as emphasized e.g. by the two-hit hyopothesis [135]; iv) think effectively at the proteome rather than single-gene level; v) account for the normal functions of APP and Aβ, as their absence within the current paradigm is conspicuous; the elaborate splicing of APP clearly occurs in the neurons for a reason; and vi) consider all manifestations of disease, including oxidative stress and metal ion imbalances, mitochondrial disease, immune system responses, and metabolic deficiencies.…”

Section: Concluding Remarks and Perspectivesmentioning

confidence: 99%

Ten Challenges of the Amyloid Hypothesis of Alzheimer’s Disease

Kepp

2016

JAD

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The inability to effectively halt or cure Alzheimer's Disease (AD), exacerbated by the recent failures of high-profile clinical trials, emphasizes the urgent need to understand the complex biochemistry of this major neurodegenerative disease. In this paper, ten central, current challenges of the major paradigm in the field, the amyloid hypothesis, are sharply formulated.These challenges together show that new approaches are necessary that address data heterogeneity, increase focus on the proteome level, use available human patient data more actively, account for the aging phenotype as a background model of the disease, unify our understanding of the interplay between genetic and non-genetic risk factors, and combine into one framework both the familial and sporadic forms of the disease.

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“…The models expressed either wild-type 94 or familial tauopathy mutant 95 forms of human tau and reproduced both cognitive impairment, phosphotau/tangle pathology and progressive neurodegeneration 96 . More recently, these models have begun to simulate "prion-like" disease transmission across neural networks 97 .…”

Section: Studying Tau Biology and Pathology In Transgenic Models Muddmentioning

confidence: 99%