APP Transgenic Mice: Their Use and Limitations

Balducci, Claudia; Forloni, Gianluigi

doi:10.1007/s12017-010-8141-7

Cited by 70 publications

(50 citation statements)

References 232 publications

(238 reference statements)

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Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

“…However, increased expression of wild-type APP, even at levels in excess of those present in Down syndrome (DS), is insufficient to cause extensive Alzheimer disease (AD) neuropathology 207 . Only mice expressing mutant APP and/or other AD-associated genes recapitulate aspects of AD neuropathology and/ or cognitive change 207 . Similarly, although altered expression of many chromosome 21 genes modifies mouse models of familial AD, whether a single extra copy of these genes is sufficient to affect pathology and behaviour remains unclear.…”

Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

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A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

Section: Box 2 Modelling Ad-ds In Mice and In Human Ipscsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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“…This has been addressed in part through the use of genetically modified mice which over-express one or more of three genes implicated in familial AD, and display both its neuropathological symptoms as well as its characteristic cognitive degeneration. Although imperfect analogues of human AD, these models provide a valuable shortcut for identifying potential early cognitive symptoms, and are regarded by many as a fundamental tool in understanding AD [4].…”

Section: Introductionmentioning

confidence: 99%

Deficits in object-in-place but not relative recency performance in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: Implications for object recognition

Bonardi

Pardon

Armstrong

2016

Behavioural Brain Research

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Performance was examined on three variants of the spontaneous object recognition (SOR) task, in 5-month old APPswe/PS1dE9 mice and wild-type littermate controls. A deficit was observed in an object-in-place (OIP) task, in which mice are preexposed to four different objects in specific locations, and then at test two of the objects swap locations (Experiment 2). Typically more exploration is seen of the objects which have switched location, which is taken as evidence of a retrieval-generated priming mechanism. However, no significant transgenic deficit was found in a relative recency (RR) task (Experiment 1), in which mice are exposed to two different objects in two separate sample phases, and then tested with both objects. Typically more exploration of the firstpresented object is observed, which is taken as evidence of a self-generated priming mechanism. Nor was there any impairment in the simplest variant, the spontaneous object recognition (SOR) task, in which mice are preexposed to one object and then tested with the familiar and a novel object. This was true regardless of whether the sample-test interval was 5 minutes (Experiment 1) or 24 hours (Experiments 1 and 2). It is argued that SOR performance depends on retrieval-generated priming as well as self-generated priming, and our preliminary evidence suggests that the retrieval-generated priming process is especially impaired in these young transgenic animals . 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 The aim of our research has been to identify early cognitive signs of AD in one specific genetic model, the double-transgenic APPswe/PS1dE9 mouse. This may be the best-characterised transgenic model of AD to date, co-expressing the mutated Swedish APP gene and also the exon-9 deleted variant of the PS1 gene [5]. Elevated levels of oligomeric Aβ in the cortex and hippocampus have been observed at 3.5 months of age in these mice; these changes are accompanied by synaptic deficits [6,7], and are also closely associated with swollen dystrophic cholinergic neurites [8].Although the amyloid plaques characteristic of AD have been reported at 4 months of age in these mice, it is only from 6 months that they are consistently observed [9]. Aβ deposition is paralleled by progressive degeneration of monaminergic [10,11] and striatal [12] neurons, and neuroinflammatory reactions [13] which mirror human AD pathology. These animals also recapitulate the age-related cognitive decline characteristic of AD [14], which is thought to depend on these neuropathological changes.The neuropathology that develops in AD in general, and in this mouse model in particular, is well specified. But precisely which aspects of this brain pathology underlie the cognitive deficits that are such a central feature of AD is still under debate [15]. In this particular mouse line, some...

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“…Novel and effective therapeutic approach for AD is urgently needed which should be tested pre-clinically in animals models that mimic familial and sporadic AD form (sAD). Widely exploited transgenic animal models of AD (Lithner et al 2011) represent the familial form of AD and do not mimic the sAD condition (Balducci and Forloni 2011). Animal model which develops insulin resistant brain state and glucose hypometabolism following the intracerebroventricular application of a betacytotoxic drug streptozotocin in small rodents and cynomolgus monkey (STZ-icv model), (Agrawal et al 2011;Grünblatt et al 2007;Lannert and Hoyer 1998;Lee et al 2014;Lester-Coll et al 2006;Plaschke and Hoyer 1993;Salkovic-Petrisic et al 2006), shares similarities with the human sAD condition (Lannert and Hoyer 1998) since insulin resistant brain state was found postmortem in sAD patients (Correia et al 2011;de la Monte and Wands 2005;Frölich et al 1998).…”

Section: Introductionmentioning

confidence: 99%