Repeated performance of spatial memory tasks ameliorates cognitive decline in APP/PS1 mice

Lonnemann, Niklas; Körte, Martin; Hosseini, Shirin

doi:10.1016/j.bbr.2022.114218

Cited by 7 publications

(4 citation statements)

References 71 publications

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“…S12A-D). Importantly, as reported [52][53][54], we noted that presymptomatic APP/PS1 mice exhibited cognitive and memory decline in Y-maze and NOR compared to aged-matched non-transgenic (NTG) mice. Interestingly, we found that MEE has no effect on cognitive performance in presymptomatic NTG mice (Fig.…”

Section: Increased Brain Metabolism After Ethanol Exposure In Presymp...supporting

confidence: 73%

Moderate ethanol exposure reduces astrocyte-induced neuroinflammatorysignaling and cognitive decline in presymptomatic APP/PS1 mice

Kang,

Lee,

Choi

et al. 2023

Preprint

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Background Alcohol use disorder (AUD) has been associated with the development of neurodegenerative diseases, including Alzheimer's disease (AD). However, recent studies demonstrate that moderate alcohol consumption may be protective against dementia and cognitive decline. Methods We examined astrocyte function, low-density lipoprotein (LDL) receptor-related protein 1 (LRP1), and the NF-κB p65 and IKK-α/β signaling pathways in modulating neuroinflammation and amyloid beta (Aβ) deposition. We assessed apolipoprotein E (ApoE) in the mouse brain using IHC and ELISA in response to moderate ethanol exposure (MEE). First, to confirm the intracerebral distribution of ApoE, we co-stained with GFAP, a marker for astrocytes that biosynthesize ApoE. We sought to investigate whether the ethanol-induced upregulation of LRP1 could potentially inhibit the activity of IL-1β and TNF-α induced IKK-α/β towards NF-κB p65, resulting in a reduction of pro-inflammatory cytokines. To evaluate the actual Aβ load in the brains of APP/PS1 mice, we performed with a specific antibody Aβ (Thioflavin S) on both air- and ethanol-exposed groups, subsequently analyzing Aβ levels. We also measured glucose uptake activity using 18F-FDG in APP/PS1 mice. Finally, we investigated whether MEE induced cognitive and memory changes using the Y maze, noble objective recognition (NOR) test, and Morris water maze (MWM). Results Our findings demonstrate that MEE reduced astrocytic glial fibrillary acidic protein (GFAP) and ApoE levels in the cortex and hippocampus in presymptomatic APP/PS1 mice. Interestingly, increased LRP1 protein expression is accompanied by dampening the IKK-α/β-NF-κB p65 pathway, resulting in decreased IL-1β and TNF-α levels in male mice. Notably, female mice show reduced anti-inflammatory cytokines, IL-4, and IL-10 levels without altering IL-1β and TNF-α concentrations. In both males and females, Aβ plaques, a hallmark of AD, were reduced in the cortex and hippocampus of ethanol-exposed presymptomatic APP/PS1 mice. Consistently, MEE increased fluorodeoxyglucose (FDG)-positron emission tomography (PET)-based brain activities and normalized cognitive and memory deficits in the APP/PS1 mice. Conclusions Our findings suggest that MEE may benefit AD pathology via modulating LRP1 expression, potentially reducing neuroinflammation and attenuating Aβ deposition. Our study implies that reduced astrocyte derived ApoE and LDL cholesterol levels are critical for attenuating AD pathology.

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Section: Increased Brain Metabolism After Ethanol Exposure In Presymp...supporting

confidence: 73%

Moderate ethanol exposure reduces astrocyte-induced neuroinflammatorysignaling and cognitive decline in presymptomatic APP/PS1 mice

Kang,

Lee,

Choi

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…Tasks such as the MWM do not require extensive repeated training periods (typically only 5-6 days), whereas operant tasks often do (Woolley and Ballard, 2005;Vorhees and Williams, 2006;Higgins and Breysse, 2008) and it may be that extensive training ameliorates deficit development. However, Lonnemann et al (2023) showed that brief (8 days) exposure every 3 months to the MWM alleviated some of the memory deficits seen in aged APP/PS1 mice, suggesting that minimal task exposure can reduce deficits. Consistent with this suggestion, APP/PS1 mice who began operant task training in a pairwise discrimination task at 3 months old, and likely had no Aβ accumulation, performed similarly to control mice, however, those who began training at 12 months of age, when Aβ accumulation is pronounced, exhibited impaired performance compared to control mice (Van den Broeck et al, 2021).…”

Section: Discussionmentioning

confidence: 97%

Acute stressors do not impair short-term memory or attention in an aged mouse model of amyloidosis

DiMarco

Harris

Savonenko

et al. 2023

Front. Behav. Neurosci.

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Memory impairment in Alzheimer’s disease patients is thought to be associated with the accumulation of amyloid-beta peptides and tau proteins. However, inconsistent reports of cognitive deficits in pre-clinical studies have raised questions about the link between amyloid-beta and cognitive decline. One possible explanation may be that studies reporting memory deficits often involve behavioral assessments that entail a high stress component. In contrast, in tasks without a high stress component transgenic mice do not consistently show declines in memory. The glucocorticoid cascade hypothesis of aging and the vicious cycle of stress framework suggest that stress exacerbates dementia progression by initiating a cycle of hypothalamic-pituitary-adrenal axis activation and subsequent brain deterioration. Using the APPswe/PS1dE9 mouse model of amyloidosis, we assessed whether stressor exposure prior to testing differentially impaired cognitive performance of aged male and female mice. As part of a larger study, mice performed a delayed match-to-position (DMTP) or a 3-choice serial-reaction time (3CSRT) task. Unexpectedly, these mice did not exhibit cognitive declines during aging. Therefore, at 73 and 74 weeks of age, we exposed mice to a predator odor or forced swim stressor prior to testing to determine if stress revealed cognitive deficits. We predicted stressor exposure would decrease performance accuracy more robustly in transgenic vs. non-transgenic mice. Acute stressor exposure increased accuracy in the DMTP task, but not in the 3CSRT task. Our data suggest that acute stressor exposure prior to testing does not impair cognitive performance in APPswe/PS1dE9 mice.

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“…Interestingly, the hippocampal systems level impairments observed here in young APP/PS1 mice precede the behavioral impairments that arise in this AD model on standard behavioral assays, where deficits of contextual memory have been reported to start around 6 months 66,67 . Thus, sampling hippocampal systems level function is likely to provide a sensitive readout for assessment of brain dysfunction and its rescue in AD models.…”

Section: Discussionmentioning

confidence: 58%

Impaired Hippocampal Reactivation Preceding Robust Aβ Deposition in a Model of Alzheimer’s Disease

Li,

Zhao,

Fassini

et al. 2024

Preprint

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Current therapeutic strategies for Alzheimer’s disease (AD) target amyloid-beta (Aβ) fibrils and high molecular weight protofibrils associated with plaques, but other bioactive species may directly contribute to neural systems failure in AD. Employing hippocampal electrophysiological recordings and dynamic calcium imaging across the sleep-wake cycle in young mice expressing human Aβ and Aβ oligomers, we reveal marked impairments of hippocampal function long before amyloid plaques predominate. In slow wave sleep (SWS), Aβ increased the proportion of hypoactive cells and reduced place-cell reactivation. During awake behavior, Aβ impaired theta-gamma phase-amplitude coupling (PAC) and drove excessive synchronization of place cell calcium fluctuations with hippocampal theta. Remarkably, the on-line impairment of hippocampal theta-gamma PAC correlated with the SWS impairment of place-cell reactivation. Together, these results identify toxic effects of Aβ on memory encoding and consolidation processes before robust plaque deposition and support targeting soluble Aβ-related species to treat and prevent AD.

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Repeated performance of spatial memory tasks ameliorates cognitive decline in APP/PS1 mice

Cited by 7 publications

References 71 publications

Moderate ethanol exposure reduces astrocyte-induced neuroinflammatorysignaling and cognitive decline in presymptomatic APP/PS1 mice

Moderate ethanol exposure reduces astrocyte-induced neuroinflammatorysignaling and cognitive decline in presymptomatic APP/PS1 mice

Acute stressors do not impair short-term memory or attention in an aged mouse model of amyloidosis

Impaired Hippocampal Reactivation Preceding Robust Aβ Deposition in a Model of Alzheimer’s Disease

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