Longitudinal assessment of cognitive function in the APPswe/PS1dE9 mouse model of Alzheimer’s-related beta-amyloidosis

Soto, Paul L.; Young, Michael E.; DiMarco, Giuliana M.; Melnikova, Tatiana; Savonenko, Alena; Harris, Breanna N.

doi:10.1016/j.neurobiolaging.2023.03.010

Cited by 3 publications

(2 citation statements)

References 71 publications

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“…Our findings are consistent with other recent reports from our laboratory. In another study, we also reported that even though transgenic mice had high brain amyloid beta burden, genotype did not adversely impact cognitive performance [67,69,136]. Others have also noted that aged transgenic mice did not show cognitive deficits [127].…”

Section: Discussionmentioning

confidence: 75%

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Harris,

Yavari,

Ramalingam

et al. 2024

Neuroendocrinology

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Introduction: Alzheimer’s disease (AD) alters neurocognitive and emotional function and causes dysregulation of multiple homeostatic processes. The leading AD framework pins amyloid beta plaques and tau tangles as primary drivers of dysfunction. However, many additional variables, including diet, stress, sex, age, and pain tolerance, interact in ways that are not fully understood to impact the onset and progression of AD pathophysiology. We asked: (1) does high-fat diet, compared to low-fat diet, exacerbate AD pathophysiology and behavioral decline? And, (2) can supplementation with eicosapentaenoic (EPA)-enriched fish oil prevent high-fat-diet-induced changes? Methods: Male and female APPswePSdE9 mice, and their non-transgenic littermates, were randomly assigned to a diet condition (low-fat, high-fat, high-fat with EPA) and followed from 2 to 10 months of age. We assessed baseline corticosterone concentration during aging, pain tolerance, cognitive function, stress coping, and corticosterone response to a stressor. Results: Transgenic mice were consistently more active than non-transgenic mice but did not perform worse on either cognitive task, even though we recently reported that these same transgenic mice exhibited metabolic changes and had increased amyloid beta. Mice fed high-fat diet had higher baseline and post-stressor corticosterone, but diet did not impact cognition or pain tolerance. Sex had the biggest influence, as female mice were consistently more active and had higher corticosterone than males. Conclusion: Overall, diet, genotype, and sex did not have consistent impacts on outcomes. We found little support for predicted interactions and correlations, suggesting diet impacts metabolic function and amyloid beta levels, but these outcomes do not translate to changes in behaviors measured here.

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Section: Discussionmentioning

confidence: 75%

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Harris,

Yavari,

Ramalingam

et al. 2024

Neuroendocrinology

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“…The object location task (OLT) was performed when the mice were 7 months of age, when cognitive decline starts [ 39 ]. The OLT was performed as described previously [ 40 ].…”

Section: Methodsmentioning

confidence: 99%

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice

Rombaut,

Schepers,

Tiane

et al. 2024

Cells

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Microglia activity can drive excessive synaptic loss during the prodromal phase of Alzheimer’s disease (AD) and is associated with lowered cyclic adenosine monophosphate (cAMP) due to cAMP phosphodiesterase 4B (PDE4B). This study aimed to investigate whether long-term inhibition of PDE4B by A33 (3 mg/kg/day) can prevent synapse loss and its associated cognitive decline in APPswe/PS1dE9 mice. This model is characterized by a chimeric mouse/human APP with the Swedish mutation and human PSEN1 lacking exon 9 (dE9), both under the control of the mouse prion protein promoter. The effects on cognitive function of prolonged A33 treatment from 20 days to 4 months of age, was assessed at 7–8 months. PDE4B inhibition significantly improved both the working and spatial memory of APPswe/PSdE9 mice after treatment ended. At the cellular level, in vitro inhibition of PDE4B induced microglial filopodia formation, suggesting that regulation of PDE4B activity can counteract microglia activation. Further research is needed to investigate if this could prevent microglia from adopting their ‘disease-associated microglia (DAM)’ phenotype in vivo. These findings support the possibility that PDE4B is a potential target in combating AD pathology and that early intervention using A33 may be a promising treatment strategy for AD.

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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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Longitudinal assessment of cognitive function in the APPswe/PS1dE9 mouse model of Alzheimer’s-related beta-amyloidosis

Cited by 3 publications

References 71 publications

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Impact of Long-Term Dietary High Fat and Eicosapentaenoic Acid on Behavior and Hypothalamic-Pituitary-Adrenal Axis Activity in Amyloidogenic APPswe/PSEN1dE9 Mice

Early Inhibition of Phosphodiesterase 4B (PDE4B) Instills Cognitive Resilience in APPswe/PS1dE9 Mice

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

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