Early Spatial Memory Impairment in a Double Transgenic Model of Alzheimer’s Disease TgF-344 AD

Pena, Stephanie L. Proskauer; Mallouppas, Konstantinos; Oliveira, André M.; Zitricky, Frantisek; Nataraj, Athira; Ježek, Karel

doi:10.3390/brainsci11101300

Cited by 9 publications

(9 citation statements)

References 38 publications

(61 reference statements)

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“…In our studies, female WT and Tg-AD rats scored better with the aPAT assessment than their male littermates. In a previous study, Tg-AD rats showed spatial memory impairment at 4 to 5 months of age using Active Allothetic Place Avoidance (AAPA), which increased at 6- to 7 months [40]. However, unlike our studies, no sex effect was observed.…”

Section: Discussioncontrasting

confidence: 71%

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Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer’s disease

Chaudry¹,

Ndukwe

Xie

et al. 2022

Preprint

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Alzheimer's disease (AD) is a progressive neurodegenerative disease and is the sixth leading cause of death in the US. AD is more prevalent in females than males. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, a comparison of the events that develop between sexes in the early-stage of AD pathology may reveal new potential targets for more effective therapeutic intervention. To address sex differences, we analyzed early stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1ΔE9) mutations that develops progressive age-dependent AD pathology similar to humans. Using active place avoidance (aPAT) tests that assess hippocampal-dependent spatial learning and memory, we found significant deficits in Tg-AD females compared to wild type females, but no significant difference between the two male genotypes. Moreover, significant sex differences were observed in that Tg-AD females outperformed Tg-AD males in several measures of the aPAT test. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques and amoeboid microglia than their Tg-AD male littermates. Furthermore, Tg-AD females experienced less hippocampal neuronal loss and had higher GluA2 subunit levels than Tg-AD males. Based on our findings, we propose that estrogen may protect females against cognitive impairment at early stages of AD by regulating GluA2 levels independently of amyloid plaque deposition and gliosis. Elucidating this potential protective mechanism of action of estrogen in AD could lead to new targets for early intervention.

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Section: Discussioncontrasting

confidence: 71%

“…These data support a neuroprotective role for estrogen in this rat model. However, other studies showed that spatial memory impairment in Tg-AD rats was evident in 6- to 7-month-old animals but no sex differences were observed [40].…”

Section: Discussionmentioning

confidence: 99%

Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer’s disease

Chaudry¹,

Ndukwe

Xie

et al. 2022

Preprint

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“…Additional sex differences in the Tg-AD rat model included reports that basal synaptic transmission deficits at CA3-CA1 synapses occur at 9 months in males and 12-months in females 55 , supporting a neuroprotective role for estrogen in this rat model. However, other studies showing spatial memory impairment in Tg-AD rats at 6- to 7-months were without sex differences 52 .…”

Section: Discussionmentioning

confidence: 91%

“…In a previous study, Tg-AD rats showed spatial navigation impairment at 4 to 5 months of age using Active Allothetic Place Avoidance (AAPA), which increased at 6 to 7 months 52 without a sex effect. In our studies, female WT and Tg-AD rats scored better with the aPAT assessment than their male littermates.…”

Section: Discussionmentioning

confidence: 95%

Females exhibit higher GluA2 levels and outperform males in active place avoidance despite increased amyloid plaques in TgF344-Alzheimer’s rats

Chaudry

Ndukwe

Xie

et al. 2022

Sci Rep

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease that is most prevalent in females. While estrogen provides neuroprotection in females, sex mediated differences in the development of AD pathology are not fully elucidated. Therefore, comparing events between sexes in early-stage AD pathology may reveal more effective therapeutic targets of intervention. To address sex differences, we analyzed early-stage 9-month male and female TgF344-AD (Tg-AD) rats, an AD model carrying the APPswe and Presenilin 1 (PS1ΔE9) mutations that develops progressive age-dependent AD pathology similar to humans. Tg-AD females significantly outperformed Tg-AD males in the active place avoidance (aPAT) test that assesses hippocampal-dependent spatial learning and memory. However, comparisons between Tg-AD male or female rats and their WT counterparts showed significant deficits for female but not male rats. Nevertheless, Tg-AD females experienced significantly less hippocampal neuronal loss with higher GluA2 subunit levels than Tg-AD males. Unexpectedly, Tg-AD females displayed higher levels of hippocampal amyloid plaques than Tg-AD males. Thus, we propose that GluA2 may provide a neuroprotective function for Tg-AD females in our rat model by mitigating cognitive impairment independently of amyloid plaques. Elucidating this protective mechanism in AD could lead to new targets for early intervention.

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“…Only a few studies have investigated cognitive and behavioral alterations in 4-month-old TgF344-AD rats. The two studies from two different facilities have observed altered spatial navigation and spatial memory in 4-month-old TgF344-AD rats using frequently used behavioral tests (e.g., Barnes Maze and Active Allothetic Place Avoidance test) [ 51 , 52 ]. Another research group observed impairments in working memory in 5-month-old TgF344-AD rats, but not at later time points [ 53 ].…”

Section: Discussionmentioning

confidence: 99%

Altered basal forebrain function during whole-brain network activity at pre- and early-plaque stages of Alzheimer’s disease in TgF344-AD rats

Berg

Adhikari²,

Verschuuren³

et al. 2022

Alz Res Therapy

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Background Imbalanced synaptic transmission appears to be an early driver in Alzheimer’s disease (AD) leading to brain network alterations. Early detection of altered synaptic transmission and insight into mechanisms causing early synaptic alterations would be valuable treatment strategies. This study aimed to investigate how whole-brain networks are influenced at pre- and early-plague stages of AD and if these manifestations are associated with concomitant cellular and synaptic deficits. Methods To this end, we used an established AD rat model (TgF344-AD) and employed resting state functional MRI and quasi-periodic pattern (QPP) analysis, a method to detect recurrent spatiotemporal motifs of brain activity, in parallel with state-of-the-art immunohistochemistry in selected brain regions. Results At the pre-plaque stage, QPPs in TgF344-AD rats showed decreased activity of the basal forebrain (BFB) and the default mode-like network. Histological analyses revealed increased astrocyte abundance restricted to the BFB, in the absence of amyloid plaques, tauopathy, and alterations in a number of cholinergic, gaba-ergic, and glutamatergic synapses. During the early-plaque stage, when mild amyloid-beta (Aβ) accumulation was observed in the cortex and hippocampus, QPPs in the TgF344-AD rats normalized suggesting the activation of compensatory mechanisms during this early disease progression period. Interestingly, astrogliosis observed in the BFB at the pre-plaque stage was absent at the early-plaque stage. Moreover, altered excitatory/inhibitory balance was observed in cortical regions belonging to the default mode-like network. In wild-type rats, at both time points, peak activity in the BFB preceded peak activity in other brain regions—indicating its modulatory role during QPPs. However, this pattern was eliminated in TgF344-AD suggesting that alterations in BFB-directed neuromodulation have a pronounced impact in network function in AD. Conclusions This study demonstrates the value of rsfMRI and advanced network analysis methods to detect early alterations in BFB function in AD, which could aid early diagnosis and intervention in AD. Restoring the global synaptic transmission, possibly by modulating astrogliosis in the BFB, might be a promising therapeutic strategy to restore brain network function and delay the onset of symptoms in AD.

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Early Spatial Memory Impairment in a Double Transgenic Model of Alzheimer’s Disease TgF-344 AD

Cited by 9 publications

References 38 publications

Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer’s disease

Females outperform males in spatial learning despite increased amyloid plaques and microgliosis in a TgF344-AD rat model of Alzheimer’s disease

Females exhibit higher GluA2 levels and outperform males in active place avoidance despite increased amyloid plaques in TgF344-Alzheimer’s rats

Altered basal forebrain function during whole-brain network activity at pre- and early-plaque stages of Alzheimer’s disease in TgF344-AD rats

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