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Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

ABSTRACT: Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid ? (A?) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of A?-centric therapeutics suggest that the amyloid hypothesis is incomplete and/or that the treatments were given too late in the course of AD, when neuronal damages were already too extensive. Hence, it is striking to see that very few studies have extensively characterized, from anatomy to behavior, the alterations associated with pre-amyloid stages in mouse models of AD amyloid pathology. To fulfill this gap, we examined memory capacities as well as hippocampal network anatomy and dynamics in young adult pre-plaque TgCRND8 mice when hippocampal A? levels are still low. We showed that TgCRND8 mice present alterations in hippocampal inhibitory networks and ? oscillations at this stage. Further, these mice exhibited deficits only in a subset of hippocampal-dependent memory tasks, which are all affected at later stages. Last, using a pharmacological approach, we showed that some of these early memory deficits were A?-independent. Our results could partly explain the limited efficacy of A?-directed treatments and favor multitherapy approaches for early symptomatic treatment for AD.

SUBMITTER: Hamm V

PROVIDER: S-EPMC5325539 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature

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Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

Hamm Valentine V Héraud Céline C Bott Jean-Bastien JB Herbeaux Karine K Strittmatter Carole C Mathis Chantal C Goutagny Romain R

Science advances 20170224 2

Alzheimer's disease (AD) is a neurodegenerative pathology commonly characterized by a progressive and irreversible deterioration of cognitive functions, especially memory. Although the etiology of AD remains unknown, a consensus has emerged on the amyloid hypothesis, which posits that increased production of soluble amyloid β (Aβ) peptide induces neuronal network dysfunctions and cognitive deficits. However, the relative failures of Aβ-centric therapeutics suggest that the amyloid hypothesis is ...[more]

PMID: 28275722

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Project description:IntroductionHonokiol (HO) exerts neuroprotective effects in several animal models of Alzheimer's disease (AD), but the poor dissolution hampers its bioavailability and therapeutic efficacy.ObjectivesA novel honokiol nanoscale drug delivery system (Nano-HO) with smaller size and excellent stability was developed in this study to improve the solubility and bioavailability of HO. The anti-AD effects of Nano-HO was determined.MethodsMale TgCRND8 mice were daily orally administered Nano-HO or HO at the same dosage (20 mg/kg) for 17 consecutive weeks, followed by assessment of the spatial learning and memory functions using the Morris Water Maze test (MWMT).ResultsOur pharmacokinetic study indicated that the oral bioavailability was greatly improved by Nano-HO. In addition, Nano-HO significantly improved cognitive deficits and inhibited neuroinflammation via suppressing the levels of TNF-α, IL-6 and IL-1β in the brain, preventing the activation of microglia (IBA-1) and astrocyte (GFAP), and reducing β-amyloid (Aβ) deposition in the cortex and hippocampus of TgCRND8 mice. Moreover, Nano-HO was more effective than HO in modulating amyloid precursor protein (APP) processing via suppressing β-secretase, as well as enhancing Aβ-degrading enzymes like neprilysin (NEP). Furthermore, Nano-HO more markedly inhibited tau hyperphosphorylation via decreasing the ratio of p-Tau (Thr 205)/tau and regulating tau-related apoptosis proteins (caspase-3 and Bcl-2). In addition, Nano-HO more markedly attenuated the ratios of p-JNK/JNK and p-35/CDK5, while enhancing the ratio of p-GSK-3β (Ser9)/GSK-3β. Finally, Nano-HO prevented the gut microflora dysbiosis in TgCRND8 mice in a more potent manner than free HO.ConclusionNano-HO was more potent than free HO in improving cognitive impairments in TgCRND8 mice via inhibiting Aβ deposition, tau hyperphosphorylation and neuroinflammation through suppressing the activation of JNK/CDK5/GSK-3β signaling pathway. Nano-HO also more potently modulated the gut microbiota community to protect its stability than free HO. These results suggest that Nano-HO has good potential for further development into therapeutic agent for AD treatment.

Project description:BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder strongly correlated with a dysfunctional immune system. Our previous results demonstrated that inactivated influenza vaccine (IIV) facilitates hippocampal neurogenesis and blocks lipopolysaccharide (LPS)-induced cognitive impairment. However, whether IIV improves cognitive deficits in an AD mouse model remains unclear. In addition, early interventions in AD have been encouraged in recent years. Here, we investigated whether IIV immunization at the preclinical stage of AD alters the brain pathology and cognitive deficits in an APP/ PS1 mouse model.MethodsWe assessed spatial learning and memory using Morris water maze (MWM). The brain ?-amyloid (A?) plaque burden and activated microglia were investigated by immunohistochemistry. Furthermore, flow cytometry was utilized to analyze the proportions of Treg cells in the spleen. A cytokine antibody array was performed to measure the alteration of cytokines in the brain and peripheral immune system.ResultsFive IIV immunizations activated microglia, reduced the A? burden and improved the cognitive impairment. Simultaneously, the IIV-induced immune response broke peripheral immunosuppression by reducing Foxp3+ regulatory T cell (Treg) activities, whereas the restoration of Treg level in the periphery using all-trans retinoic acid (ATRA) blunted the protective effects of IIV on A? burden and cognitive functions. Interestingly, IIV immunization might increase proinflammatory and anti-inflammatory cytokine expression in the brain of APP/PS1 mice, enhanced microglial activation, and enhanced the clustering and phagocytosis of A?, thereby creating new homeostasis in the disordered immune microenvironment.ConclusionsAltogether, our results suggest that early multiple IIV immunizations exert a beneficial immunomodulatory effect in APP/PS1 mice by breaking Treg-mediated systemic immune tolerance, maintaining the activation of microglia and removing of A? plaques, eventually improving cognitive deficits.

Project description:BACKGROUND:Knock-in (KI) mouse models of Alzheimer's disease (AD) that endogenously overproduce A? without non-physiological overexpression of amyloid precursor protein (APP) provide important insights into the pathogenic mechanisms of AD. Previously, we reported that AppNL-G-F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited emotional alterations before the onset of definitive cognitive deficits. To determine whether these mice exhibit deficits in learning and memory at more advanced ages, we compared the Morris water maze performance of AppNL-G-F and AppNL mice, which harbor only the Swedish mutation, with that of wild-type (WT) C57BL/6J mice at the age of 24 months. To correlate cognitive deficits and neuroinflammation, we also examined A? plaque formation and reactive gliosis in these mice. RESULTS:In the Morris water maze, a spatial task, 24-month-old AppNL-G-F/NL-G-F mice exhibited significantly poorer spatial learning than WT mice during the hidden training sessions, but similarly to WT mice during the visible training sessions. Not surprisingly, AppNL-G-F/NL-G-F mice also exhibited spatial memory deficits both 1 and 7 days after the last training session. By contrast, 24-month-old AppNL/NL mice had intact spatial learning and memory relative to WT mice. Immunohistochemical analyses revealed that 24-month-old AppNL-G-F/NL-G-F mice developed massive A? plaques and reactive gliosis (microgliosis and astrocytosis) throughout the brain, including the cortex and hippocampus. By contrast, we observed no detectable brain pathology in AppNL/NL mice despite overproduction of human A?40 and A?42 in their brains. CONCLUSIONS:A? plaque formation, followed by sustained neuroinflammation, is necessary for the induction of definitive cognitive deficits in App-KI mouse models of AD. Our data also indicate that introduction of the Swedish mutation alone in endogenous APP is not sufficient to produce either AD-related brain pathology or cognitive deficits in mice.

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Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

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Differential contribution of APP metabolites to early cognitive deficits in a TgCRND8 mouse model of Alzheimer's disease.

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