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Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice.

ABSTRACT: We have previously demonstrated hippocampal hyperglutamatergic signaling occurs prior to plaque accumulation in AβPP/PS1 mice. Here, we evaluate 2-Amino-6-(trifluoromethoxy) benzothiazole (riluzole) as an early intervention strategy for Alzheimer's disease (AD), aimed at restoring glutamate neurotransmission prior to substantial Beta amyloid (Aβ) plaque accumulation and cognitive decline. Male AβPP/PS1 mice, a model of progressive cerebral amyloidosis, were treated with riluzole from 2-6 months of age. Morris water maze, in vivo electrochemistry, and immunofluorescence were performed to assess cognition, glutamatergic neurotransmission, and pathology, respectively, at 12 months. Four months of prodromal riluzole treatment in AβPP/PS1 mice resulted in long-lasting procognitive effects and attenuated glutamatergic tone that was observed six months after discontinuing riluzole treatment. Riluzole-treated AβPP/PS1 mice had significant improvement in long-term memory compared to vehicle-treated AβPP/PS1 mice that was similar to normal aging C57BL/6J control mice. Furthermore, basal glutamate concentration and evoked-glutamate release levels, which were elevated in vehicle-treated AβPP/PS1 mice, were restored to levels observed in age-matched C57BL/6J mice in AβPP/PS1 mice receiving prodromal riluzole treatment. Aβ plaque accumulation was not altered with riluzole treatment. This study supports that interventions targeting the glutamatergic system during the early stages of AD progression have long-term effects on disease outcome, and importantly may prevent cognitive decline. Our observations provide preclinical support for targeting glutamate neurotransmission in patients at risk for developing AD. Read the Editorial Highlight for this article on page 399.

SUBMITTER: Hascup KN

PROVIDER: S-EPMC7902360 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundExposure to benzo(a)pyrene (BaP) was associated with cognitive impairments and some Alzheimer's disease (AD)-like pathological changes. However, it is largely unknown whether BaP exposure participates in the disease progression of AD.ObjectivesTo investigate the effect of BaP exposure on AD progression and its underlying mechanisms.MethodsBaP or vehicle was administered to 4-month-old APPswe/PS1dE9 transgenic (APP/PS1) mice and wildtype (WT) mice for 2 months. Learning and memory ability and exploratory behaviors were evaluated 1 month after the initiation/termination of BaP exposure. AD-like pathological and biochemical alterations were examined 1 month after 2-month BaP exposure. Levels of soluble beta-amyloid (Aβ) oligomers and the number of Aβ plaques in the cortex and the hippocampus were quantified. Gene expression profiling was used to evaluate alternation of genes/pathways associated with AD onset and progression. Immunohistochemistry and Western blot were used to demonstrate neuronal loss and neuroinflammation in the cortex and the hippocampus. Treatment of primary neuron-glia cultures with aged Aβ (a mixture of monomers, oligomers, and fibrils) and/or BaP was used to investigate mechanisms by which BaP enhanced Aβ-induced neurodegeneration.ResultsBaP exposure induced progressive decline in spatial learning/memory and exploratory behaviors in APP/PS1 mice and WT mice, and APP/PS1 mice showed severer behavioral deficits than WT mice. Moreover, BaP exposure promoted neuronal loss, Aβ burden and Aβ plaque formation in APP/PS1 mice, but not in WT mice. Gene expression profiling showed most robust alteration in genes and pathways related to inflammation and immunoregulatory process, Aβ secretion and degradation, and synaptic formation in WT and APP/PS1 mice after BaP exposure. Consistently, the cortex and the hippocampus of WT and APP/PS1 mice displayed activation of microglia and astroglia and upregulation of inducible nitric oxide synthase (iNOS), glial fibrillary acidic protein (GFAP), and NADPH oxidase (three widely used neuroinflammatory markers) after BaP exposure. Furthermore, BaP exposure aggravated neurodegeneration induced by aged Aβ peptide in primary neuron-glia cultures through enhancing NADPH oxidase-derived oxidative stress.ConclusionOur study showed that chronic exposure to environmental pollutant BaP induced, accelerated, and exacerbated the progression of AD, in which elevated neuroinflammation and NADPH oxidase-derived oxidative insults were key pathogenic events.

Project description:The symptomologies of Alzheimer's disease (AD) develop over decades suggesting modifiable lifestyle factors may contribute to disease pathogenesis. In humans, hyperinsulinemia associated with type 2 diabetes mellitus increases the risk for developing AD and both diseases share similar age-related etiologies including amyloidogenesis. Since we have demonstrated that soluble Aβ42 elicits glutamate release, we wanted to understand how diet-induced insulin resistance alters hippocampal glutamate dynamics, which are important for memory formation and consolidation. Eight to twelve-week-old C57BL/6J and AβPP/PS1 mice were placed on either a low-fat diet or high-fat diet (HFD) for 8 months. A HFD led to significant weight increases as well as impaired insulin sensitivity, glucose tolerance, and learning in both C57BL/6J and AβPP/PS1 mice. AβPP/PS1 low-fat diet mice had elevated hippocampal basal as well as stimulus-evoked glutamate release that was further increased with consumption of a HFD. Immunohistochemistry indicated an increase in vesicular glutamate transporter 1 and glial fibrillary acidic protein density in hippocampal subregions corresponding with this elevated extracellular glutamate. While no differences in hippocampal plaque load were observed, the elevated astrogliotic response surrounding the plaques in AβPP/PS1 HFD mice may have been a compensatory mechanism to control plaque accumulation. These data support that AβPP/PS1 mice have chronically elevated extracellular glutamate that is exacerbated by a HFD and that modifiable lifestyle factors such as obesity-induced insulin resistance can contribute to AD pathogenesis. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* and for *Open Data* because it made the data publicly available. The data can be accessed at https://osf.io/5whvu (figures for data) and https://osf.io/gd5vf (materials and methods). The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/. Cover Image for this issue: doi: 10.1111/jnc.14490.

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Riluzole attenuates glutamatergic tone and cognitive decline in AβPP/PS1 mice.

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