Journal: Journal of Alzheimer's disease : JAD
LMTM is being developed as a treatment for AD based on inhibition of tau aggregation.
Reduced bone mineral density (BMD) and its clinical sequelae, osteoporosis, occur at a much greater rate the rate in patients with Alzheimer’s disease (AD), often emerging early in the disease before significant cognitive decline is seen. Reduced BMD translates to increased bone fracture risk, decreased quality of life, and increased mortality for AD patients. However, the mechanism responsible for this observation is unclear. We hypothesize that bone loss is an additional component of an AD prodrome, changes that emerge prior to dementia and are mediated by dysfunction of the central serotonergic pathways. We characterized the skeletal phenotype of htau mice that express human forms of the microtubule-associated protein tau that become pathologically hyperphosphorylated in AD. Using radiographic densitometry, we measured BMD in female and male htau mice from 2-6 months of age-time-points prior to the presence of significant tauopathy in the hippocampal/entorhinal regions characteristic of this model. We found a significantly reduced BMD phenotype in htau mice that was most pronounced in males. Using western blotting and immunofluorescence, we showed overall reduced tryptophan hydroxylase (TPH) protein in htau brainstem and a 70% reduction in TPH-positive cells in the dorsal raphe nucleus (DRN)-a pivotal structure in the regulation of the adult skeleton. Elevations of hyperphosphorylated tau (ptau) proteins were also measured in brainstem, and co-labeled immunofluorescence studies showed presence of ptau in TPH-positive cells of the DRN as early as 4 months of age in htau mice. Together, these findings demonstrate that reduced BMD occurs earlier than overt degeneration in a tau-based AD model and that pathological changes in the tau phosphorylation occur in the serotonin-producing neurons of the brainstem raphe in these mice. This illuminates a need to define a mechanistic relationship between bone loss and serotonergic deficits in early AD.
To better understand the association of alcohol intake with cognitively healthy longevity (CHL), we explored the association between amount and frequency of alcohol intake and CHL among 1,344 older community-dwelling adults. Alcohol intake was assessed by questionnaire in 1984-1987. Cognitive function was assessed in approximate four-year intervals between 1988 and 2009. Multinomial logistic regression, adjusting for multiple lifestyle and health factors, was used to examine the association between alcohol consumption and CHL (living to age 85 without cognitive impairment), survival to age 85 with cognitive impairment (MMSE score >1.5 standard deviations below expectation for age, sex, and education), or death before age 85. Most participants (88%) reported some current alcohol intake; 49% reported a moderate amount of alcohol intake, and 48% reported drinking near-daily. Relative to nondrinkers, moderate and heavy drinkers (up to 3 drinks/day for women and for men 65 years and older, up to 4 drinks/day for men under 65 years) had significantly higher adjusted odds of survival to age 85 without cognitive impairment (p's < 0.05). Near-daily drinkers had 2-3 fold higher adjusted odds of CHL versus living to at least age 85 with cognitive impairment (odds ratio (OR) = 2.06; 95% confidence interval (CI): 1.21, 3.49) or death before 85 (OR = 3.24; 95% CI: 1.92, 5.46). Although excessive drinking has negative health consequences, these results suggest that regular, moderate drinking may play a role in cognitively healthy longevity.
Genetics and lifestyle independently determine dementia risk, but the interaction is unclear. We assessed the interactive relationship of apolipoprotein E (APOE) genotype and physical exercise on dementia risk over a 5-year period in 1,646 older adults from the Canadian Study of Health and Aging who were dementia-free at baseline. Physical exercise moderated the relationship between genotype and dementia (p < 0.01). Specifically, for APOE ɛ4 non-carriers, the odds of developing dementia were higher in non-exercisers than exercisers (OR = 1.98, 95% CI = 1.44, 2.71, p < 0.001), whereas, for APOE ɛ4 carriers, the odds of developing dementia were not significantly different between non-exercisers and exercisers (OR = 0.71, 95% CI = 0.46, 1.31, p = 0.34). Given that most individuals are not at genetic risk, physical exercise may be an effective strategy for preventing dementia.
Few studies have evaluated the impact of marijuana use on regional cerebral blood flow.
Tau oligomers have been shown to transmit tau pathology from diseased neurons to healthy neurons through seeding, tau misfolding, and aggregation that is thought to play an influential role in the progression of Alzheimer’s disease (AD) and related tauopathies. To develop a small molecule therapeutic for AD and related tauopathies, we have developed in vitro and cellular assays to select molecules inhibiting the first step in tau aggregation, the self-association of tau into oligomers. In vivo validation studies of an optimized lead compound were independently performed in the htau mouse model of tauopathy that expresses the human isoforms of tau without inherited tauopathy mutations that are irrelevant to AD. Treated mice did not show any adverse events related to the compound. The lead compound significantly reduced the level of self-associated tau and total and phosphorylated insoluble tau aggregates. The dose response was linear with respect to levels of compound in the brain. A confirmatory study was performed with male htau mice that gave consistent results. The results validated our screening approach by showing that targeting tau self-association can inhibit the entire tau aggregation pathway by using the selected and optimized lead compound whose activity translated from in vitro and cellular assays to an in vivo model of tau aggregation.
Studies have reported that females have widespread increases in regional cerebral blood flow, but the studies were relatively small and inconsistent.
Aggregates of hyperphosphorylated tau (PHF-tau), such as neurofibrillary tangles, are linked to the degree of cognitive impairment in Alzheimer’s disease. We have developed a novel PHF-tau targeting positron emission tomography imaging agent, [F-18]-T807, which may be useful for imaging Alzheimer’s disease and other tauopathies. Here, we describe the first human brain images with [F-18]-T807.
We examined the cross-sectional association between mushroom intake and mild cognitive impairment (MCI) using data from 663 participants aged 60 and above from the Diet and Healthy Aging (DaHA) study in Singapore. Compared with participants who consumed mushrooms less than once per week, participants who consumed mushrooms >2 portions per week had reduced odds of having MCI (odds ratio = 0.43, 95% CI 0.23-0.78, p = 0.006) and this association was independent of age, gender, education, cigarette smoking, alcohol consumption, hypertension, diabetes, heart disease, stroke, physical activities, and social activities. Our cross-sectional data support the potential role of mushrooms and its bioactive compounds in delaying neurodegeneration.
The specific CB2 cannabinoid receptor agonist JWH-133 induced cognitive improvement in double AβPP/PS1 transgenic mice, a genetic model of Alzheimer’s disease. This effect was more pronounced when administered at the pre-symptomatic rather than the early symptomatic stage. The cognitive improvement was associated with decreased microglial reactivity and reduced expression of pro-inflammatory cytokines IL-1β, IL-6, TNFα, and IFNγ. In addition, JWH-133 reduced the expression of active p38 and SAPK/JNK, increased the expression of inactive GSK3β, and lowered tau hyperphosphorylation at Thr181 in the vicinity of amyloid-β plaques. Moreover, JWH-133 produced a decrease in the expression of hydroxynonenal adducts, and enhanced the expression of SOD1 and SOD2 around plaques. In contrast, the chronic treatment with JWH-133 failed to modify the amyloid-β production or deposition in cortex and hippocampus. In conclusion, the present study lends support to the idea that stimulation of CB2 receptors ameliorates several altered parameters in Alzheimer’s disease such as impaired memory and learning, neuroinflammation, oxidative stress damage and oxidative stress responses, selected tau kinases, and tau hyperphosphorylation around plaques.