Molecular mechanisms underlying synaptic dysfunction in Aging Alzheimer's disease and Diabetes
Type of Degreedissertation
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Alzheimer’s disease (AD) and diabetes (DB) contribute to the development of early brain aging and cognitive dysfunction. Mechanistic basis of cognitive dysfunction in AD and DB is not well elucidated. Resistance to age related cognitive decline has been observed in growth hormone deficient, long-lived Ames dwarf mice. These mice show reduced circulating levels of growth hormone (GH) and insulin growth factor-1 (IGF-1); however, they have increased levels of these hormones in the hippocampus, a part of the brain where memory is encoded and consolidated. The hippocampal glutamatergic and cholinergic systems play a vital role in synaptic plasticity mechanisms of learning and memory. Therefore, we investigated the expression of glutamtergic synaptic markers and cholinergic and inflammatory enzymatic activity in the hippocampus of the Ames dwarf mice. We found an increase in postsynaptic glutamate receptor expression as well as increased cholineacetyl transferase and lactate dehydrogenase activity. We have also found elevated acetylcholine and enhanced postsynaptic glutamatergic activity in the hippocampus of these dwarf mice, which results in the development of improved synaptic plasticity and cognitive function. AD is associated with the early aging of the brain and results in the development of cognitive impairment. Amyloid beta (Aβ) is one of the major hallmarks of AD; the molecular mechanism by which Aβ alters glutamatergic system and impairs cognitive function in the early stages of AD is not well understood. To better understand the effects of Aβ upon the development of AD, we intracranially infused Aβ (1-42) into wild type mice and found that diminished postsynaptic glutamate receptors that are crucial for learning and memory. Such finding implicates that Aβ, directly disrupts cognitive function and synaptic plasticity via attenuating postsynaptic glutamatergic transmission prior to development of neurodegeneration. Recent studies suggested direct link between AD and diabetes type 2. To better understand the mechanism of how insulin resistance impairs cognitive function, we utilized a transgenic type 2 diabetic mouse model (Leptin receptor knock out db/db mice). The nuclear receptor PPARγ plays a key role in metabolic regulation by modulating whole body glucose homeostasis and insulin sensitivity. Recently, PPARγ has also been implicated to have anti-inflammatory and neuroprotective effects in mouse models of AD. Consequently, we investigated the effects of PPARγ activation on diabetes-induced deficits in spatial and recognition memory in db/db mice. We found that pharmacological activation of PPARγ ameliorates diabetes-induced impairment of spatial and recognition memory and also synaptic transmission and LTP. These data can be explained by our findings that PPARγ activation enhanced the postsynaptic glutamate receptor expression in the db/db mouse model. In addition, we also found an increase in the insulin substrate-2 protein (IRS-2) and its effector proteins, which are involved in the insulin signaling cascade. Moreover, we found that synaptic plasticity master regulatory transcription factor CREB binding protein (CBP) also increased by PPARγ activation. These data offers a plausible hypothesis that PPARγ enhances synaptic plasticity and cognitive function by modulating insulin signaling pathway and synaptic plasticity associated transcription factors leading to improved glutamatergic synaptic transmission. Our findings suggest that molecular targets such as PPARγ may offer potential therapeutic targets for DB, AD and aging induced cognitive impairment.