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Removing Neuronal PRAS40 Exacerbates Alzheimer's Disease Pathology in a Mouse Model

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Alzheimer’s disease (AD) is characterized by the aberrant accumulation and aggregation of proteins that in turn contribute to learning and memory deficits. The mammalian target of rapamycin (mTOR) plays an essential role in regulating the synthesis and degradation of proteins

Alzheimer’s disease (AD) is characterized by the aberrant accumulation and aggregation of proteins that in turn contribute to learning and memory deficits. The mammalian target of rapamycin (mTOR) plays an essential role in regulating the synthesis and degradation of proteins that contribute to cell growth and learning and memory. Hyperactivity of mTOR can cause detrimental effects to protein homeostasis and has been linked to AD. The proline-rich Akt-substrate 40 kDa (PRAS40) is a negative regulator of mTOR, as it binds to mTOR directly, reducing its activity. Upon phosphorylation, PRAS40 detaches from mTOR thereby releasing its inhibitory effects. Increased phosphorylation of PRAS40, and a subsequent increase in mTOR activity has been linked to diabetes, cancer, and other conditions; however, PRAS40’s direct role in the pathogenesis of AD is still unclear. To investigate the role of PRAS40 in AD pathology, we generated a PRAS40 conditional knockout mouse model and, using a neuronal-specific Cre recombinase, selectively removed PRAS40 from APP/PS1 mice. Removing neuronal PRAS40 exacerbated Abeta levels and plaque load but paradoxically had no significant effects on mTOR signaling. Mechanistically, the increase in Abeta pathology was linked to a decrease in autophagy function. Our data highlight a primary role of PRAS40 in the pathogenesis of AD.

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Date Created
2019-05

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Elucidating the Effects of PRAS40 on Learning and Memory

Description

The mammalian target of rapamycin (mTOR) is integral in regulating cell growth as it maintains a homeostatic balance of proteins by modulating their synthesis and degradation. In the brain, mTOR regulates protein-driven neuroplastic changes that modulate learning and memory. Nevertheless,

The mammalian target of rapamycin (mTOR) is integral in regulating cell growth as it maintains a homeostatic balance of proteins by modulating their synthesis and degradation. In the brain, mTOR regulates protein-driven neuroplastic changes that modulate learning and memory. Nevertheless, upregulation of mTOR can cause detrimental effect in spatial memory and synaptic plasticity. The proline-rich Akt-substrate 40 kDa (PRAS40) is a key negative regulator of mTOR, as it binds mTOR and directly reduces its activity. To investigate the role of PRAS40 on learning and memory, we generated a transgenic mouse model in which we used the tetracycline-off system to regulate the expression of PRAS40 specifically in neurons of the hippocampus. After induction, we found that mice overexpressing PRAS40 performed better than control mice in the Morris Water Maze behavioral test. We further show that the improvement in memory was associated with a decrease in mTOR signaling, an increase in dendritic spines in hippocampal pyramidal neurons, and an increase in the levels of brain-derived neurotrophic factor (BDNF), a neurotrophin necessary for learning and memory. This is the first evidence that shows that increasing PRAS40 in the mouse brain enhances learning and memory deficits.

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Date Created
2018-05