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Vascular dementia (VaD) is caused by chronic decreases in brain blood flow and accounts for 15-20% of dementia cases worldwide. In contrast to Alzheimer's disease (AD), no effective drug treatments are currently available for VaD. Previous studies have suggested that oxidative stress and neuroinflammation in the brain play important roles in the pathogenesis of VaD. Honokiol (HKL) is a well-known bioactive and nutraceutical compound that can act as an antioxidant and anti-inflammatory molecule. HKL can protect against memory impairments in AD mouse models. In this study, we explored whether the application of HKL was also protective against the insult of chronic cerebral hypoperfusion (CCH) in rats. We found that HKL supplementation prevented the memory impairments in the inhibitory avoidance step-down and Morris water maze tasks in CCH rats. HKL also suppressed the levels of oxidative stress and inflammation in CCH rats. Moreover, HKL prevented dendritic spines abnormalities in CCH rats. We also found that HKL inhibited the activity of GSK-3β, which may be critical for the neuroprotective activity of HKL. Thus, our study demonstrated the protective role of HKL in VaD.

Previous studies demonstrate that patients with sleep disorders are at risk of developing Alzheimer's disease (AD), with the mechanism unknown. It is suggested that acute sleep deprivation induces an increase of amyloid-β (Aβ), the major pathological agent in AD, in the cerebrospinal fluid (CSF). In the present study, we recruited 23 patients with chronic insomnia aged between 46 to 67 years and 23 healthy controls aged between 43 to 67 years. We investigated the CSF levels of Aβ and tau, another pathological hallmark in the AD pathogenesis. We found that CSF Aβ42 levels were significantly increased in insomnia patients. However, no significant difference was found in Aβ40, total tau (t-Tau), and phosphorylated tau (p-Tau) between the two groups. Furthermore, we found that CSF Aβ40 and Aβ42 levels are significantly correlated with the sleep quality, as reflected by the Pittsburgh Sleep Quality Index (PSQI) scores. But no significant correlation was found in CSF t-Tau and p-Tau levels with PSQI. Our results indicate that chronic sleep disorders may induce the disruption of Aβ metabolism in the brain, thus increase the risk for developing AD.

The p75 neurotrophin receptor (p75NTR) is an amyloid-β (Aβ) receptor that both mediates Aβ neurotoxicity and regulates Aβ production and deposition, thus playing an important role in the pathogenesis of Alzheimer's disease (AD). The extracellular domain of p75NTR (p75ECD), consisting of four cysteine-rich repeat domains (CRDs), was recently reported to be an endogenous anti-Aβ scavenger to block p75NTR-mediated neuronal death and neurite degeneration signaling of Aβ and pro-neurotrophins. Identification of the specific Aβ binding domains of p75NTR is crucial for illuminating their interactions and the etiology of AD. CRDs of p75ECD were obtained by expression of recombinant plasmids or direct synthesis. Aβ aggregation inhibiting test and immunoprecipitation assay were applied to locate the specific binding domains of Aβ to p75ECD. The Aβ neurotoxicity antagonistic effects of different CRDs were examined by cytotoxicity experiments including neurite outgrowth assay, propidium iodide (PI) staining, and MTT assay. In the Aβ aggregation inhibiting test, the fluorescence intensity in the CRD2 and CRD4 treatment groups was significantly lower than that in the CRD1 and CRD3 treatment groups. Immunoprecipitation assay and western blot confirmed that Aβ could bind to CRD2 and CRD4. Besides, CRD2 and CRD4 antagonized Aβ neurotoxicity suggested by longer neurite length, less PI labelled cells, and higher cell viability than the control group. Our results indicate that CRD2 and CRD4 are Aβ binding domains of p75NTR and capable of antagonizing Aβ neurotoxicity, and therefore are potential therapeutic targets to block the interaction of Aβ and p75NTR in the pathogenesis of AD.

Previous studies have suggested that cardiovascular functions might play a critical role in Alzheimer's disease (AD) pathogenesis. However, the relationship among heart function, blood flow of cerebral vessels, and AD remains unclear. In the present study, AD patients (n = 34) and age- and gender-matched cognitively normal controls (n = 34) were recruited. Demographic and comorbidity information was collected. The ejection fraction was measured using echocardiography, and the mean velocity, pulsatility index (PI), and resistance index (RI) of the basilar artery (BA), left terminal internal carotid artery (LTICA), and right terminal internal carotid artery (RTICA) were measured using transcranial Doppler. The data of lacunae, white matter changes, and plaques in the aortic arch and carotid arteries were collected from brain magnetic resonance imaging and computed tomography angiography images. Compared with normal controls, AD patients had lower ejection fractions and cerebral blood flow velocities and higher RI and PI in the BA, LTICA, and RTICA, as well as more plaques in the aortic and carotid arteries. In the multivariate logistic regression analysis, the ejection fraction and the mean velocity of the BA and LTICA were independently associated with AD after adjusting for age, gender, education, vascular risk factors, arterial plaques, and brain ischemic lesions detected in the brain images. These findings suggest that heart function and vascular condition may play important roles in AD pathogenesis. Improving cardiovascular functions could be a promising approach for the prevention and treatment of AD.

To investigate whether vascular risk affects the progression of Alzheimer's disease (AD), 415 AD patients aged 65 years old and over without cerebrovascular diseases were enrolled and administered with a structured interview to assess demography, vascular risk factors, and cognitive and functional status at baseline, and 324 AD patients were followed up annually for 5 years. A mixed random effects regression model was used to identify the association between vascular risk, individual vascular risk factors, and the progression of AD. After adjusting for confounding factors, AD patients with vascular risk had faster cognitive and functional decline rates than the subjects without such risk factors. Individual vascular risk factors including hypertension and diabetes mellitus, transient ischemic attack and cerebrovascular accident during the follow-up were independently associated with the progression of AD. Our findings suggest that vascular risk aggravates the progression of AD and may be involved in the etiologic process of AD. As such, control of vascular risk may slow down the progression of AD.