Background: Exercise and diet control are fundamental approaches to metabolic conditions caused by high fat diet (HFD). Results: HFD-induced memory deficit and A␤ deposition were more ameliorated in the exercise-than in the diet controlinduced mice. Conclusion: Exercise was more effective than diet control in preventing HFD-induced AD development. Significance: Exercise has the highest priority in the prevention of AD.

The pathogenesis of Alzheimer's disease (AD) is tightly associated with metabolic dysfunctions. In particular, a potential link between type 2 diabetes (T2DM) and AD has been suggested epidemiologically, clinically, and experimentally, and some studies have suggested that exercise or dietary intervention reduces risk of cognitive decline. However, there is little solid molecular evidence for the effective intervention of metabolic dysfunctions for prevention of AD. In the present study, we established the AD model mice with diabetic conditions through high-fat diet (HFD) to examine the effect of environmental enrichment (EE) on HFD-induced AD pathophysiology. Here, we demonstrated that HFD markedly deteriorated memory impairment and increased β-amyloid (Aβ) oligomers as well as Aβ deposition in amyloid precursor protein (APP) transgenic mice, which was reversed by exposure to an enriched environment for 10 weeks, despite the continuation of HFD. These studies provide solid evidence that EE is a useful intervention to ameliorate behavioral changes and AD pathology in HFD-induced aggravation of AD symptoms in APP transgenic mice.

Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer disease. N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapse. Here we report that the functional disruption of N-cadherin-mediated cell contact activated p38 MAPK in murine primary neurons, followed by neuronal death. We further observed that treatment with A␤ 42 decreased cellular N-cadherin expression through NMDA receptors accompanied by increased phosphorylation of both p38 MAPK and Tau in murine primary neurons. Moreover, expression levels of phosphorylated p38 MAPK were negatively correlated with that of N-cadherin in human brains. Proteomic analysis of human brains identified a novel interaction between N-cadherin and JNK-associated leucine zipper protein (JLP), a scaffolding protein involved in the p38 MAPK signaling pathway. We demonstrated that N-cadherin expression had an inhibitory effect on JLP-mediated p38 MAPK signal activation by decreasing the interaction between JLP and p38 MAPK in COS7 cells. Also, this study demonstrated a novel physical and functional association between N-cadherin and p38 MAPK and suggested neuroprotective roles of cadherinbased synaptic contact. The dissociation of N-cadherin-mediated synaptic contact by A␤ may underlie the pathological basis of neurodegeneration such as neuronal death, synaptic loss, and Tau phosphorylation in Alzheimer disease brain.Alzheimer disease (AD) 2 is pathologically characterized by the presence of amyloid ␤-peptide (A␤) and neurofibrillary tangles in the neocortex and hippocampus. Insoluble A␤ fibrillar aggregates found in senile plaques have long been considered to cause the neurodegeneration of AD. On the other hand, synaptic loss is another pathological hallmark of AD, which strongly correlates with the severity of cognitive impairment better than senile plaques or neurofibrillary tangles (1). Interestingly, recent studies from AD mouse models have shown that learning impairment and synaptic dysfunction become apparent before the formation of plaques, suggesting the hypothesis that soluble A␤ causes "synaptic failure" before plaques develop and neuron death occurs (2). Converging lines of evidence suggest that natural soluble A␤ oligomers trigger synaptic loss (3). Thus, in addition to the investigation of molecular mechanisms, which develop senile plaques and neurofibrillary tangles, research focusing on synaptic dysfunction is important to clarify the earliest pathology in AD.Presenilin (PS) 1/2 is the essential catalytic component of ␥-secretase proteolytic complex (4, 5), which is responsible for the final cleavage of amyloid precursor protein to generate A␤ peptides. Mutations in PS1 have been known as the most common cause of autosomal dominant familial Alzheimer disease (6 -8). Interestingly, PS1 binds to N-cadherin, which is an essential molecule for synaptic contact and is abundantly localized in hippocampal synapses ...

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High fat diet (HFD) is prevalent in many modern societies and HFD-induced metabolic condition is a growing concern worldwide. It has been previously reported that HFD clearly worsens cognitive function in amyloid precursor protein (APP) transgenic mice. On the other hand, we have demonstrated that voluntary exercise in an enriched environment is an effective intervention to rescue HFD-induced β-amyloid (Aβ) deposition and memory deficit. However, it had been unclear whether consumption of HFD after exercising abolished the beneficial effect of exercise on the inhibition of Alzheimer's disease (AD) pathology. To examine this question, we exposed wild type (WT) and APP mice fed with HFD to exercise conditions at different time periods. In our previous experiment, we gave HFD to mice for 20 weeks and subjected them to exercise during weeks 10–20. In the present study, mice were subjected to exercise conditions during weeks 0–10 or weeks 5–15 while being on HFD. Interestingly, we found that the effect of exercise during weeks 0–10 or weeks 5–15 on memory function was not abolished in WT mice even if they kept having HFD after finishing exercise. However, in APP transgenic mice, HFD clearly disrupted the effect of exercise during weeks 0–10 or weeks 5–15 on memory function. Importantly, we observed that the level of Aβ oligomer was significantly elevated in the APP mice that exercised during weeks 0–10: this might have been caused by the up-regulation of Aβ production. These results provide solid evidence that continuation of exercise is necessary to rescue HFD-induced aggravation of cognitive decline in the pathological setting of AD.

Presenilin 1 (PS1), a causative molecule of familial Alzheimer's disease (AD), is known to be an unprimed substrate of glycogen synthase kinase 3 β (GSK3β) [Twomey and McCarthy (2006) FEBS Lett 580:4015-4020] and is phosphorylated at serine 353, 357 residues in its cytoplasmic loop region [Kirschenbaum et al. (2001) J Biol Chem 276:7366-7375]. In this report, we investigated the effect of PS1 phosphorylation on AD pathophysiology and obtained two important results--PS1 phosphorylation increased amyloid β (Aβ) 42/40 ratio, and PS1 phosphorylation was enhanced in the human AD brains. Interestingly, we demonstrated that PS1 phosphorylation promoted insulin receptor (IR) cleavage and the IR intracellular domain (IR ICD) generated by γ-secretase led to a marked transactivation of Akt (PKB), which down-regulated GSK3β activity. Thus, the cleavage of IR by γ-secretase can inhibit PS1 phosphorylation in the long run. Taken together, our findings indicate that PS1 phosphorylation at serine 353, 357 residues can play a pivotal role in the pathology of AD and that the dysregulation of this mechanism may be causally associated with its pathology.