Astrocytic cytoskeletal atrophy in the medial prefrontal cortex of a triple transgenic mouse model of Alzheimer’s disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the loss of cognitive functions, reflecting pathological damage to the medial prefrontal cortex (mPFC) as well as to the hippocampus and the entorhinal cortex. Astrocytes maintain the internal homeostasis of the CNS and are fundamentally involved in neuropathological processes, including AD. Here, we analysed the astrocytic cytoskeletal changes within the mPFC of a triple transgenic mouse model of AD (3 · Tg-AD) by measuring the surface area and volume of glial fibrillary acidic protein (GFAP)-positive profiles in relation to the build-up and presence of amyloid-b (Ab), and compared the results with those found in non-transgenic control animals at different ages. 3 · Tg-AD animals showed clear astroglial cytoskeletal atrophy, which appeared at an early age (3 months; 33% and 47% decrease in GFAP-positive surface area and volume, respectively) and remained throughout the disease progression at 9, 12 and 18 months old (29% and 36%; 37% and 35%; 43% and 37%, respectively). This atrophy was independent of Ab accumulation, as only a few GFAP-positive cells were localized around Ab aggregates, which suggests no direct relationship with Ab toxicity. Thus, our results indicate that the progressive reduction in astrocytic branching and domain in the mPFC can account for the integrative dysfunction leading to the cognitive deficits and memory disturbances observed in AD.

Astroglial calcium signalling in Alzheimer's disease

“…before considerable accumulation of extracellular β-amyloid and formation of senile plaques) and they were characterised by decreased complexity of astrocytes (which had less primary and secondary processes) and by reduction on the size of profiles of astrocytes labelled with antibodies against GFAP or glutamine synthetase. [99,100,103,104]. The atrophic changes in astrocytes developed in a particular spatio-temporal pattern with the earliest signs of atrophy observed in the entorhinal cortex (at 1 months of age); at 3 months of age morphological atrophy of astrocytes was identified in the prefrontal cortex, whereas in the hippocampus the atrophic changes were evident from 9 to 12 months of age [99,100,103].…”

“…Astroglial reactivity was not uniform throughout the brain; formation of extracellular β-amyloid deposits and emergence of senile plaques failed to induce reactive astrogliosis in entorhinal and prefrontal cortices [99,100]. In the triple transgenic (3xTG) AD mice over-expressing mutant genes for amyloid precursor protein (APP Swe ), presenilin 1 (PS1 M146V ) and microtubule-associated protein Tau (Tau P301L ), [101]and in PDAPP-J20 mice carrying the Swedish and Indiana human mutations of APP [102] astroglial atrophy was identified throughout the brain [99,100,[103][104][105][106]. Astrodegenerative changes were found at the early pre-symptomatic stages (i.e.…”

“…[99,100,103,104]. The atrophic changes in astrocytes developed in a particular spatio-temporal pattern with the earliest signs of atrophy observed in the entorhinal cortex (at 1 months of age); at 3 months of age morphological atrophy of astrocytes was identified in the prefrontal cortex, whereas in the hippocampus the atrophic changes were evident from 9 to 12 months of age [99,100,103]. Expression of glutamine synthetase was generally decreased in hippocampal reactive astrocytes, indicating possible deficits in glutamateglutamine shuttle [107]; in the entorhinal cortex, however, expression of glutamine synthetase seems to be preserved [108].…”

Ethanol deregulates Mecp2/MeCP2 in differentiating neural stem cells via interplay between 5-methylcytosine and 5-hydroxymethylcytosine at the Mecp2 regulatory elements

“…In agreement with these previous reports, we observed changes in neuronal morphology and glial size. As a measurement of glial size, we analyzed the surface area of GFAP + cells, as other research groups have done to represent the size of glia (Kulijewicz-Nawrot et al, 2012;Rodriguez et al, 2013). Immunofluorescent labeling of binge ethanol-treated astrocytes at D2 showed reduced cellular size (~2.1-fold, p < 0.0001) relative to the control untreated D2 cells (Fig.…”

Mitochondrial Function in Alzheimer’s Disease: Focus on Astrocytes

“…In addition, an impairment in Aβ uptake and neuronal support was demonstrated in old 5xFAD astrocytes [60]. In another mouse model of AD, the 3xTG-AD mice (with three FAD mutations in genes encoding APP, PSEN1 and tau) atrophy of astrocytes was described to start early, at the age of 3 months [61,62]. The double transgenic APPswePS1dE9 AD mouse model has revealed a decline in normal functioning of old astrocytes leading to diminution of neuronal support [63].…”