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APP mouse models for Alzheimer's disease preclinical studies

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      Abstract

      Animal models of human diseases that accurately recapitulate clinical pathology are indispensable for understanding molecular mechanisms and advancing preclinical studies. The Alzheimer's disease ( AD) research community has historically used first‐generation transgenic (Tg) mouse models that overexpress proteins linked to familial AD ( FAD), mutant amyloid precursor protein ( APP), or APP and presenilin ( PS). These mice exhibit AD pathology, but the overexpression paradigm may cause additional phenotypes unrelated to AD. Second‐generation mouse models contain humanized sequences and clinical mutations in the endogenous mouse App gene. These mice show Aβ accumulation without phenotypes related to overexpression but are not yet a clinical recapitulation of human AD. In this review, we evaluate different APP mouse models of AD, and review recent studies using the second‐generation mice. We advise AD researchers to consider the comparative strengths and limitations of each model against the scientific and therapeutic goal of a prospective preclinical study.

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      Most cited references 153

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      Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

      The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).
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        The amyloid hypothesis of Alzheimer's disease at 25 years

        Abstract Despite continuing debate about the amyloid β‐protein (or Aβ hypothesis, new lines of evidence from laboratories and clinics worldwide support the concept that an imbalance between production and clearance of Aβ42 and related Aβ peptides is a very early, often initiating factor in Alzheimer's disease (AD). Confirmation that presenilin is the catalytic site of γ‐secretase has provided a linchpin: all dominant mutations causing early‐onset AD occur either in the substrate (amyloid precursor protein, APP) or the protease (presenilin) of the reaction that generates Aβ. Duplication of the wild‐type APP gene in Down's syndrome leads to Aβ deposits in the teens, followed by microgliosis, astrocytosis, and neurofibrillary tangles typical of AD. Apolipoprotein E4, which predisposes to AD in > 40% of cases, has been found to impair Aβ clearance from the brain. Soluble oligomers of Aβ42 isolated from AD patients' brains can decrease synapse number, inhibit long‐term potentiation, and enhance long‐term synaptic depression in rodent hippocampus, and injecting them into healthy rats impairs memory. The human oligomers also induce hyperphosphorylation of tau at AD‐relevant epitopes and cause neuritic dystrophy in cultured neurons. Crossing human APP with human tau transgenic mice enhances tau‐positive neurotoxicity. In humans, new studies show that low cerebrospinal fluid (CSF) Aβ42 and amyloid‐PET positivity precede other AD manifestations by many years. Most importantly, recent trials of three different Aβ antibodies (solanezumab, crenezumab, and aducanumab) have suggested a slowing of cognitive decline in post hoc analyses of mild AD subjects. Although many factors contribute to AD pathogenesis, Aβ dyshomeostasis has emerged as the most extensively validated and compelling therapeutic target.
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          TREM2 variants in Alzheimer's disease.

          Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice. We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease. Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).
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            Author and article information

            Affiliations
            [ 1 ] Laboratory for Proteolytic Neuroscience RIKEN Brain Science Institute Wako Japan
            [ 2 ] Department of Neurology and Neurological Science Graduate School of Medicine Tokyo Medical and Dental University Tokyo Japan
            [ 3 ] Division of Neurogeriatrics Department of Neurobiology, Care Sciences and Society Center for Alzheimer Research Karolinska Institutet Huddinge Sweden
            [ 4 ] Department of Neuroscience and Pathobiology Research Institute of Environmental Medicine Nagoya University Nagoya Japan
            [ 5 ] Dementia Research Institute University College London London UK
            [ 6 ] Department for Neurosciences KU Leuven Leuven Belgium
            [ 7 ] VIB Center for Brain and Disease Research Leuven Belgium
            [ 8 ] Reta Lila Research Laboratories and the Department of Molecular Neuroscience University College London Institute of Neurology London UK
            [ 9 ] Department of Cell and Molecular Biology Feinberg School of Medicine Northwestern University Chicago IL USA
            Author notes
            [* ] Corresponding author. Tel: +81 48 4621111 (ext 7613); E‐mail: hiroki.sasaguri@ 123456riken.jp

            Corresponding author. Tel: +81 48 4679715; E‐mail: saido@ 123456brain.riken.jp

            Contributors
            ORCID: http://orcid.org/0000-0003-2550-9156, hiroki.sasaguri@riken.jp
            ORCID: http://orcid.org/0000-0003-1970-6903, saido@brain.riken.jp
            Journal
            EMBO J
            EMBO J
            10.1002/(ISSN)1460-2075
            EMBJ
            embojnl
            The EMBO Journal
            John Wiley and Sons Inc. (Hoboken )
            0261-4189
            1460-2075
            02 August 2017
            01 September 2017
            02 August 2017
            : 36
            : 17 ( doiID: 10.1002/embj.v36.17 )
            : 2473-2487
            28768718 5579350 10.15252/embj.201797397 EMBJ201797397
            © 2017 The Authors. Published under the terms of the CC BY 4.0 license

            This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

            Counts
            Figures: 4, Tables: 1, Pages: 15, Words: 14413
            Product
            Funding
            Funded by: Ministry of Education, Culture, Sports, Science, and Technology (MEXT)
            Award ID: 26290019
            Award ID: 15K19036
            Funded by: RIKEN
            Funded by: Japan Science and Technology Agency Precursory Research for Embryonic Science and Technology
            Award ID: JPMJPR1285
            Funded by: Strategic Research Program for Brain Sciences
            Award ID: 17dm0107071h0002
            Funded by: Japan Agency for Medical Research and Development (AMED)
            Funded by: Alzheimerfonden
            Funded by: Hållstens forskningsstiftelse
            Funded by: Svenska Forskningsrådet Formas (Swedish Research Council Formas)
            Funded by: HHS | National Institutes of Health (NIH)
            Award ID: AG022560
            Award ID: AG030142
            Categories
            Review
            Review
            Custom metadata
            2.0
            embj201797397
            01 September 2017
            Converter:WILEY_ML3GV2_TO_NLMPMC version:5.1.9 mode:remove_FC converted:01.09.2017

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