Calretinin Interneurons are Early Targets of Extracellular Amyloid-β Pathology in PS1/AβPP Alzheimer Mice Hippocampus

Abstract

Abstract. Specific neuronal networks are preferentially affected in the early stages of Alzheimer's disease (AD). The distinct subpopulations of hippocampal inhibitory GABAergic system have been shown to display differential vulnerability to neurodegeneration in AD. We have previously reported a substantial loss of SOM/NPY interneurons, whereas those expressing parvalbumin were unaltered, in the hippocampus of 6 month-old PS1/AβPP transgenic mice. In the present study, we now investigated the pathological changes of hippocampal calretinin (CR) interneurons in this PS1/AβPP model from 2 to 12 months of age. The total number of CR-immunoreactive inhibitory cells was determined by stereology in CA1 and CA2/3 subfields. Our findings show a substantial decrease (35%-45%) of CR-positive interneurons in both hippocampal subfields of PS1/AβPP mice at very early age (4 months) compared to age-matched control mice. This decrease was accompanied by a reduced CR mRNA content as determined by quantitative RT-PCR. However, the number of another hippocampal CR-positive population (belonging to Cajal-Retzius cells) was not affected. The selective early loss of CR-interneurons was parallel to the appearance of extracellular Aβ deposits, preferentially in CR-axonal fields, and the formation of dystrophic neurites. This specific GABAergic subpopulation plays a crucial role in the generation of synchronous rhythmic activity in hippocampus by controlling other interneurons. Therefore, early alterations of hippocampal inhibitory functionality in AD, caused by select CR-cells neurodegeneration, could result in cognitive impairments seen in initial stages of the disease.

Predominant loss of glutamatergic terminal markers in a β-amyloid peptide model of Alzheimer's disease

“…This lack of evident changes in GABAergic terminals is in line with the recent report showing that the number of GABAergic neurons is not altered in early phases of AD (Krantic et al, 2012) being only modified at later stages of AD (Hardy et al, 1987b;Bell et al, 2003León-Espinosa et al, 2012). However, this finding should not hinder the evidence that there are early changes in the activity of GABAergic neurons in early AD (Baglietto-Vargas et al, 2010;Verret et al, 2012), typified by a desynchronization of hippocampal circuits (reviewed in Palop and Mucke, 2010) which correction with levetiracetam results in the preservation of memory performance (Sanchez et al, 2012). Since this is proposed to result from the dysfunction of particular populations of interneurons (BagliettoVargas et al, 2010;Verret et al, 2012), it is possible that putative changes in the presynaptic density and function of these particular populations may not be measurable with a global marker of GABAergic terminals such as vGAT.…”

“…Indeed, the cholinergic hypothesis of AD assumes a particular susceptibility of cholinergic neurons (reviewed in Q1 Bartus et al, 1982;Auld et al, 2002), reflecting a primary affection of cholinergic terminals in cortical regions early in AD (Hu et al, 2003). More recently, several studies have suggested a particular vulnerability of glutamatergic synapses Kirvell et al, 2006;Kashani et al, 2008;Minkeviciene et al, 2008;Proctor et al, 2010), whereas other studies have instead reported that it is GABAergic neurons that are initially affected in early AD (Agarwal et al, 2008;Baglietto-Vargas et al, 2010;Verret et al, 2012).…”

Vulnerability of calbindin, calretinin and parvalbumin in a transgenic/knock-in APPswe/PS1dE9 mouse model of Alzheimer disease together with disruption of hippocampal neurogenesis

“…Immunohistochemistry against DCX, a commonly used neuroblast marker that correlates well with the number of newly generated neurons in the hippocampus (Brown et al, 2003), supported these observations. Our data are in line with previously published studies demonstrating altered neurogenesis in AD (Baglietto-Vargas et al, 2010;Moon et al, 2014;Tatebayashi, 2003).…”

Age-dependent Accumulation of Soluble Amyloid β (Aβ) Oligomers Reverses the Neuroprotective Effect of Soluble Amyloid Precursor Protein-α (sAPPα) by Modulating Phosphatidylinositol 3-Kinase (PI3K)/Akt-GSK-3β Pathway in Alzheimer Mouse Model

“…In this sense, the selective inhibitory effect of A␤ oligomers (NGF Ͼ IGF-1 ϭ insulin Ͼ BDNF) might contribute to this decreased signal and, in consequence, be implicated in the preferential vulnerability of the cholinergic system observed in AD. It has also been demonstrated that A␤ oligomers could directly bind to p75NTR (55,58) producing the formation of neuritic dystrophies (also observed in our model) (30,59,60) and the activation of c-Jun kinases mediating cell degeneration (61). Thus, the appearance of A␤ oligomers could actively decrease the trophic support, interacting with trophic receptors (this work), and/or increase the toxic signaling activating death receptors such as p75NTR.…”