Hippocampal interneuron loss in an APP/PS1 double mutant mouse and in Alzheimer's disease

Department of Neuroscience, Maastricht University, 6200 MD, Maastricht, The Netherlands.
Brain Structure and Function (Impact Factor: 5.62). 03/2010; 214(2-3):145-60. DOI: 10.1007/s00429-010-0242-4
Source: PubMed


Hippocampal atrophy and neuron loss are commonly found in Alzheimer's disease (AD). However, the underlying molecular mechanisms and the fate in the AD hippocampus of subpopulations of interneurons that express the calcium-binding proteins parvalbumin (PV) and calretinin (CR) has not yet been properly assessed. Using quantitative stereologic methods, we analyzed the regional pattern of age-related loss of PV- and CR-immunoreactive (ir) neurons in the hippocampus of mice that carry M233T/L235P knocked-in mutations in presenilin-1 (PS1) and overexpress a mutated human beta-amyloid precursor protein (APP), namely, the APP(SL)/PS1 KI mice, as well as in APP(SL) mice and PS1 KI mice. We found a loss of PV-ir neurons (40-50%) in the CA1-2, and a loss of CR-ir neurons (37-52%) in the dentate gyrus and hilus of APP(SL)/PS1 KI mice. Interestingly, comparable PV- and CR-ir neuron losses were observed in the dentate gyrus of postmortem brain specimens obtained from patients with AD. The loss of these interneurons in AD may have substantial functional repercussions on local inhibitory processes in the hippocampus.

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    • "). Marked loss in CR-IR cells was previously reported in the hippocampus of mice with experimental AD and in human patients (Takahashi et al., 2010). Our results demonstrate a significant age-dependent vulnerability of CR + cells in the SGZ, a site of adult neurogenesis. "
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    ABSTRACT: The pathogenesis of Alzheimer Disease (AD) is characterized by accumulation of β-amyloid protein in the brain (in both soluble and insoluble forms) and by the presence of intracellular neurofibrillary tangles (NFTs), leading to neurotoxicity. The exact mechanisms whereby Aβ triggers brain alterations are unclear. However, accumulating evidence suggests that a deregulation of Ca(2+) signaling may play a major role in disease progression. Calcium-buffering proteins, including calbindin-D28K (CB), calretinin (CR) and parvalbumin (PV), may offer neuroprotection by maintaining calcium homeostasis. Although marked reductions in these proteins have been observed in the brains of mice and humans with AD, their contribution to AD pathology remains unclear. The aim of the present study was to analyze distribution patterns of CB(+,) CR(+) and PV(+) interneurons in different areas of the hippocampus, a brain region that is severely affected in AD. A transgenic knock-in APPswe/PS1dE9 mouse model of familial AD was used. The data were obtained from the brains of 3- and 12- month-old animals. These ages roughly correspond to an early mature adult (prior to clinical manifestations) and a late middle-age (clinical symptoms readily detectable) phase in human AD patients. Immunostaining revealed increases in CB and PV immunoreactivity (IR) in hippocampus of 3-month-old transgenic mice, compared to wild-type animals. Possibly, these proteins are upregulated in an attempt to control cellular homeostasis and synaptic plasticity. However, the pattern of CB-IR was reversed in 12-month-old animals, potentially indicating a loss of cellular capacity to respond to pathophysiological processes. In addition, at this age, a noticeable increase in PV-IR was observed, suggesting the presence of hippocampal network hyperactivity in older AD-like mice. Our results indicate that CaBP(+) neuronal subpopulations play a role in adult neurogenesis and in AD pathology, particularly at early disease stages, suggesting that these neurons may serve as potential predictors of future AD in non-demented individuals. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jun 2015 · Experimental gerontology
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    • "PV is an essential element of learning networks. The decrease in their cell number occurs in some cases of epilepsy (Castro et al., 2011; Dinocourt et al., 2003), Alzheimer's disease (Brady and Mufson, 1997; Takahashi et al., 2010), schizophrenia (Nullmeier et al., 2011; Zhang and Reynolds, 2002), and other disorders such as dementia with Lewis bodies (Bernstein et al., 2011). Although the rhythmicity Fig. 4 – Distributions of CB-IR, CR-IR and PV-IR neurons in the polymorphic layer of the dentate gyrus of the primate Sapajus apella. "
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    Full-text · Article · Apr 2015 · Brain research
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    • "The model we used mimics many features of AD, including robust neuroinflammation, synaptic damage and neuronal loss in the hippocampus as has also been shown in our institution. The loss of CR neurons that has been recently reported (Baglietto-Vargas et al., 2010; Stepanichev et al., 2006; Takahashi et al., 2010) refers to a different experimental condition, where PS1/AbetaPP transgenic mice were used and the observations were carried out on 2–12 month old mice. However, even if the differences could be species-specific, we agree with these authors that CR-containing hippocampal neurons are early targets of βA pathology, induced in our study by central administration. "
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