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.

Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid beta deposition in amyloid protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid beta(1-40) (Abeta(1-40)), amyloid beta(1-42) (Abeta(1-42)), as well as Western blotting and filter assay for Abeta. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid beta(1-40) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Abeta(1-42) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Abeta(1-40) and Abeta(1-42) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Abeta fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Abeta fibrils and induced Abeta deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.

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 ...

The diagnosis of idiopathic normal pressure hydrocephalus (iNPH) is sometimes complicated by concomitant Alzheimer's disease (AD) pathology. The purpose of the present study is to identify an iNPH-specific cerebrospinal fluid (CSF) biomarker dynamics and to assess its ability to differentiate iNPH from AD. Total tau (t-tau), tau phosphorylated at threonine 181 (p-tau), amyloid-β (Aβ) 42 and 40, and leucine-rich α-2-glycoprotein (LRG) were measured in 93 consecutive CSF samples consisting of 55 iNPH (46 tap test responders), 20 AD, 11 corticobasal syndrome, and 7 spinocerebeller disease. Levels of t-tau and p-tau were significantly decreased in iNPH patients especially in tap test responders compared to AD. Correlation was observed between Mini-Mental State Examination scores and Aβ42 in AD (R = 0.44) and mildly in iNPH (R = 0.28). Although Aβ42/40 ratio showed no significant difference between iNPH and AD (p = 0.08), the levels of Aβ40 and Aβ42 correlated positively with each other in iNPH (R = 0.73) but much less in AD (R = 0.26), suggesting that they have discrete amyloid clearance and pathology. LRG levels did not differ between the two. Thus, our study shows that although CSF biomarkers of iNPH patients can be affected by concomitant tau and/or amyloid pathology, CSF t-tau and p-tau are highly useful for differentiation of iNPH and AD.

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.