Dataset Information

?FosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease.

ABSTRACT: Alzheimer's disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ?FosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ?FosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering histone deacetylation. Acute histone deacetylase (HDAC) inhibition or inhibition of ?FosB activity restored c-Fos induction and improved cognition in AD mice. Administration of seizure-inducing agents to nontransgenic mice also resulted in ?FosB-mediated suppression of c-Fos, suggesting that this mechanism is not confined to AD mice. These results explain observations that c-Fos expression increases after acute neuronal activity but decreases with chronic activity. Moreover, these results indicate a general mechanism by which seizures contribute to persistent cognitive deficits, even during seizure-free periods.

SUBMITTER: Corbett BF

PROVIDER: S-EPMC5785235 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease.

Corbett Brian F BF You Jason C JC Zhang Xiaohong X Pyfer Mark S MS Tosi Umberto U Iascone Daniel M DM Petrof Iraklis I Hazra Anupam A Fu Chia-Hsuan CH Stephens Gabriel S GS Ashok Annie A AA Aschmies Suzan S Zhao Lijuan L Nestler Eric J EJ Chin Jeannie J

Cell reports 20170701 2

Alzheimer's disease (AD) is characterized by cognitive decline and 5- to 10-fold increased seizure incidence. How seizures contribute to cognitive decline in AD or other disorders is unclear. We show that spontaneous seizures increase expression of ΔFosB, a highly stable Fos-family transcription factor, in the hippocampus of an AD mouse model. ΔFosB suppressed expression of the immediate early gene c-Fos, which is critical for plasticity and cognition, by binding its promoter and triggering hist ...[more]

PMID: 28700937

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Project description:Tau cleavage plays a crucial role in the onset and progression of Alzheimer's Disease (AD), a widespread neurodegenerative disease whose incidence is expected to increase in the next years. While genetic and familial forms of AD (fAD) occurring early in life represent less than 1%, the sporadic and late-onset ones (sAD) are the most common, with ageing being an important risk factor. Intracerebroventricular (ICV) infusion of streptozotocin (STZ)-a compound used in the systemic induction of diabetes due to its ability to damage the pancreatic β cells and to induce insulin resistance-mimics in rodents several behavioral, molecular and histopathological hallmarks of sAD, including memory/learning disturbance, amyloid-β (Aβ) accumulation, tau hyperphosphorylation, oxidative stress and brain glucose hypometabolism. We have demonstrated that pathological truncation of tau at its N-terminal domain occurs into hippocampi from two well-established transgenic lines of fAD animal models, such as Tg2576 and 3xTg mice, and that it's in vivo neutralization via intravenous (i.v.) administration of the cleavage-specific anti-tau 12A12 monoclonal antibody (mAb) is strongly neuroprotective. Here, we report the therapeutic efficacy of 12A12mAb in STZ-infused mice after 14 days (short-term immunization, STIR) and 21 days (long-term immunization regimen, LTIR) of i.v. delivery. A virtually complete recovery was detected after three weeks of 12A12mAb immunization in both novel object recognition test (NORT) and object place recognition task (OPRT). Consistently, three weeks of this immunization regimen relieved in hippocampi from ICV-STZ mice the AD-like up-regulation of amyloid precursor protein (APP), the tau hyperphosphorylation and neuroinflammation, likely due to modulation of the PI3K/AKT/GSK3-β axis and the AMP-activated protein kinase (AMPK) activities. Cerebral oxidative stress, mitochondrial impairment, synaptic and histological alterations occurring in STZ-infused mice were also strongly attenuated by 12A12mAb delivery. These results further strengthen the causal role of N-terminal tau cleavage in AD pathogenesis and indicate that its specific neutralization by non-invasive administration of 12A12mAb can be a therapeutic option for both fAD and sAD patients, as well as for those showing type 2 diabetes as a comorbidity.

Project description:To understand multifactorial conditions such as Alzheimer's disease (AD) we need brain signatures that predict the impact of multiple pathologies and their interactions. To help uncover the relationships between pathology affected brain circuits and cognitive markers we have used mouse models that represent, at least in part, the complex interactions altered in AD, while being raised in uniform environments and with known genotype alterations. In particular, we aimed to understand the relationship between vulnerable brain circuits and memory deficits measured in the Morris water maze, and we tested several predictive modeling approaches. We used in vivo manganese enhanced MRI traditional voxel based analyses to reveal regional differences in volume (morphometry), signal intensity (activity), and magnetic susceptibility (iron deposition, demyelination). These regions included hippocampus, olfactory areas, entorhinal cortex and cerebellum, as well as the frontal association area. The properties of these regions, extracted from each of the imaging markers, were used to predict spatial memory. We next used eigenanatomy, which reduces dimensionality to produce sets of regions that explain the variance in the data. For each imaging marker, eigenanatomy revealed networks underpinning a range of cognitive functions including memory, motor function, and associative learning, allowing the detection of associations between context, location, and responses. Finally, the integration of multivariate markers in a supervised sparse canonical correlation approach outperformed single predictor models and had significant correlates to spatial memory. Among a priori selected regions, expected to play a role in memory dysfunction, the fornix also provided good predictors, raising the possibility of investigating how disease propagation within brain networks leads to cognitive deterioration. Our cross-sectional results support that modeling approaches integrating multivariate imaging markers provide sensitive predictors of AD-like behaviors. Such strategies for mapping brain circuits responsible for behaviors may help in the future predict disease progression, or response to interventions.

Dataset Information

?FosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease.

Publications

ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer's Disease.

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