Approximately 5 million Americans currently suffer from Alzheimers disease (AD) a neurodegenerative disorder characterized by progressive impairment of cognitive function and emotional and sleep disturbances. This laboratory has developed cell culture and mouse models of AD, and have used these models to elucidate the biochemical and molecular events responsible for neuronal dysfunction and death in AD. Our findings suggest that during aging neurons become increasingly prone to dysfunction as a result of impaired cellular energy metabolism and destabilization of calcium-regulating systems. Amyloid beta-peptide can exacerbate these age-related changes in neurons resulting in their degeneration and consequent cognitive deficits. Membrane lipid peroxidation appears to play an important role in amyloidogenic processing of the amyloid precursor protein as the lipid peroxidation product 4-hydroxynonenal covalently modifies the protein nicastrin and thereby increases gamma-secretase activity. We have also found that redox enzymes in the plasma membrane play important roles in protecting neurons against membrane lipid peroxidation and Abeta toxicity. The latter findings reveal previously unknown molecular targets for the development of novel therapeutic interventions in AD. We have found that dietary restriction can reduce amyloid deposition and protect neurons from being damaged and killed in animal models of AD, and that this beneficial effect of dietary restriction involves stimulation of the production of brain-derived neurotrophic factor (BDNF). Antidepressant serotonin reuptake inhibitors can reduce amyloid deposition and improve cognitive function in a mouse model of AD, suggesting a potential prophylactic/therapeutic use of such drugs. In addition, we found that a drug called diazoxide, previously used to treat hypertension,reduces amyloid and tau pathologies and improves cognitive function in our 3xTgAD mouse model of AD. In addition, dietary supplementation with nicotinamide retards the disease process in a mouse model of AD by a mechanism involving sustenance of neuronal energy levels and enhanced clearance of abnormal forms of amyloid and tau. We have shown that diabetes causes a deficit in cognitive function which is associated with impaired hippocampal synaptic plasticity and neurogenesis;exercise and dietary energy restriction can counteract these adverse effects of diabetes. Our recent findings suggest that an excitatory imbalance, resulting from reduced GABAergic inhibition, is an early and pivotal event in AD pathogenesis. We recently demonstrated a therapeutic benefit of drugs used to improve glycemic control in animal models of diabetes and Alzheimer's disease, and we have initiated a clinical trial of one of these drugs, Exenatide, in human subjects with mild cognitive impairment or early stage Alzheimer's disease. In other studies we have provided evidence that activation of certain toll-like receptors (TLRs) in neurons and glial cells renders neurons vulnerable to Abeta toxicity and energy deprivation. Moreover,TLRs 2, 3 and 4 have interesting and disparate roles in the regulation of behaviors, including learning and memory and anxiety. Additional findings suggest that there is a defect in DNA base excision repair in brain cells of AD patients and subjects with amnestic mild cognitive impairment. Interestingly, physiological levels of activation of glutamate receptors and BDNF can enhance DNA repair, suggesting that exercise, dietary energy restriction and cognitive challenges (all of which increase BDNF levels) may also enhance the ability of neurons to repair damaged DNA. We recently found that 3xTgAD mice (which develop amyloid and tau pathologies, and cognitive deficits) attend less accurately to short, spatially unpredictable stimuli when the attentional demand of the task was high, and also showed a general tendency to make more perseverative responses than wild-type mice. The attentional impairment of 3xTgAD mice was comparable to that of AD patients in two aspects: first, although 3xTgAD mice initially responded as accurately as wild-type mice, they subsequently failed to sustain their attention over the duration of the task;second, the ability to sustain attention was enhanced by the cholinesterase inhibitor donepezil (Aricept). These findings demonstrate that familial AD mutations not only affect memory, but also cause significant impairments in attention, a cognitive domain supported by the prefrontal cortex and its afferents. Because attention deficits are likely to affect memory encoding and other cognitive abilities, our findings have important consequences for the assessment of disease mechanisms and therapeutics in animal models of AD. We found that cerebral cortical neurons respond to chronic suppression of excitability by downregulating the expression of genes and their encoded proteins involved in inhibitory transmission (GABAergic and somatostatin) and calcium signaling;alterations in pathways involved in lipid metabolism and energy management are also features of silenced neuronal networks. A molecular fingerprint strikingly similar to that of diminished network activity occurs in the human brain during aging and in AD, and opposite changes occur in response to activation of N-methyl-D-aspartate (NMDA) and brain-derived neurotrophic factor (BDNF) receptors in cultured cortical neurons and in mice in response to an enriched environment or electroconvulsive shock. Our findings suggest that reduced inhibitory neurotransmission during aging and in AD may be the result of compensatory responses that, paradoxically, render the neurons vulnerable to calcium-mediated degeneration. In another study we used 3xTgAD mice and nontransgenic control mice to test for an affect of chronic mild social stress on blood glucose, plasma glucocorticoids, plasma insulin, anxiety, and hippocampal amyloid -particle (A), phosphorylated tau (ptau), and BDNF levels. Despite the fact that both control and 3xTgAD mice experienced rises in corticosterone during episodes of mild social stress, at the end of the 6-week stress period 3xTgAD mice displayed increased anxiety, elevated levels of A oligomers and intraneuronal A, and decreased brain-derived neurotrophic factor levels, whereas control mice did not. Findings suggest 3xTgAD mice are more vulnerable than control mice to chronic psychosocial stress, and that such chronic stress exacerbates A accumulation and impairs neurotrophic signaling. In collaboration with extramural investigators we found that soluble amyloid precursor protein- (sAPP-) decreases A generation by directly associating with -site APP-converting enzyme (BACE)1, thereby modulating APP processing. Whereas specifically targeting sAPP- using antibodies enhances A production;in transgenic mice with AD-like pathology, sAPP- overexpression decreases -amyloid plaques and soluble A. In support, immunoneutralization of sAPP- increases APP amyloidogenic processing in these mice. Given our current findings, and because a number of risk factors for sporadic AD serve to lower levels of sAPP- in brains of AD patients, inadequate sAPP- levels may be sufficient to polarize APP processing towards the amyloidogenic, A-producing route. Therefore, restoration of sAPP- or enhancement of its association with BACE may be viable strategies to ameliorate imbalances in APP processing that can lead to AD pathogenesis.
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