The Amyloid Precursor Protein Controls Adult Hippocampal Neurogenesis through GABAergic Interneurons

Wang, Baiping; Wang, Zilai; Sun, Lu; Yang, Li; Li, Hongmei; Cole, Allysa L.; Rodriguez-Rivera, Jennifer; Lu, Hui-Chen; Zheng, Hui

doi:10.1523/jneurosci.2848-14.2014

Cited by 92 publications

(80 citation statements)

References 40 publications

(21 reference statements)

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“…We speculated that regional differences in basal APP expression or APP processing could explain these phenotypic differences. This interpretation would be in line with a recent publication, which reported APP to be predominantly expressed by interneurons in the DG (Wang et al, 2014). …”

Section: Introductionsupporting

confidence: 91%

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco

Paul

Schlaudraff

et al. 2016

Front. Mol. Neurosci.

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The physiological role of amyloid precursor protein (APP) has been extensively investigated in the rodent hippocampus. Evidence suggests that APP plays a role in synaptic plasticity, dendritic and spine morphogenesis, neuroprotection and—at the behavioral level—hippocampus-dependent forms of learning and memory. Intriguingly, however, studies focusing on the role of APP in synaptic plasticity have reported diverging results and considerable differences in effect size between the dentate gyrus (DG) and area CA1 of the mouse hippocampus. We speculated that regional differences in APP expression could underlie these discrepancies and studied the expression of APP in both regions using immunostaining, in situ hybridization (ISH), and laser microdissection (LMD) in combination with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. In sum, our results show that APP is approximately 1.7-fold higher expressed in pyramidal cells of Ammon’s horn than in granule cells of the DG. This regional difference in APP expression may explain why loss-of-function approaches using APP-deficient mice revealed a role for APP in Hebbian plasticity in area CA1, whereas this could not be shown in the DG of the same APP mutants.

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Section: Introductionsupporting

confidence: 91%

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco

Paul

Schlaudraff

et al. 2016

Front. Mol. Neurosci.

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“…These genes may also play a part in AD-DS, perhaps via an effect on APP processing or on cognitive reserve. APP overexpression may also affect CNS function independently of the production and accumulation of Aβ, because the expression level of full-length APP influences neurogenesis, neuronal migration, axonal growth and the maintenance of the excitatoryinhibitory balance 172,173 . How the changes in CNS function caused by trisomy of chromosome 21 affect neurodegeneration in AD-DS is little understood and is a crucial area of future research.…”

Section: Neuronal Development and Functionmentioning

confidence: 99%

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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“…Interestingly, APP ¡/¡ mice showed enhanced proliferation of dentate gyrus progenitor cells, but an impaired maintenance of newborn neurons. 39 No detrimental effect on neurogenesis could be established in mice carrying human APP with the Swedish double mutation, which has been inserted in a homozygous fashion into the endogenous gene locus ("knock-in"). These mice do not develop detectable extracellular amyloid pathology up to an age of 20 months.…”

Section: App Expression and Its Impact On Neurogenesismentioning

confidence: 99%

Altered neurogenesis in mouse models of Alzheimer disease

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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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The Amyloid Precursor Protein Controls Adult Hippocampal Neurogenesis through GABAergic Interneurons

Cited by 92 publications

References 40 publications

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

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

Altered neurogenesis in mouse models of Alzheimer disease

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