No abstract

Resveratrol is a polyphenol that is mainly found in grapes and red wine and has been reported to be a caloric restriction (CR) mimetic driven by Sirtuin 1 (SIRT1) activation. Resveratrol increases metabolic rate, insulin sensitivity, mitochondrial biogenesis and physical endurance, and reduces fat accumulation in mice. In addition, resveratrol may be a powerful agent to prevent age-associated neurodegeneration and to improve cognitive deficits in Alzheimer's disease (AD). Moreover, different findings support the view that longevity in mice could be promoted by CR. In this study, we examined the role of dietary resveratrol in SAMP8 mice, a model of age-related AD. We found that resveratrol supplements increased mean life expectancy and maximal life span in SAMP8 and in their control, the related strain SAMR1. In addition, we examined the resveratrol-mediated neuroprotective effects on several specific hallmarks of AD. We found that longterm dietary resveratrol activates AMPK pathways and pro-survival routes such as SIRT1 in vivo. It also reduces cognitive impairment and has a neuroprotective role, decreasing the amyloid burden and reducing tau hyperphosphorylation.

Current mouse models of Alzheimer's disease (AD) are restricted to the expression of AD-related pathology associated with specific mutations present in early-onset familial AD and thus represent <5% of AD cases. To date there are no mouse lines that model late-onset/age-related AD, the feature which accounts for the vast majority of cases. As such, based on current mutation-associated models, the chronology of events that lead to the disease in the aged population is difficult to establish. However, published data show that senescence-accelerated mouse (SAMP8), as a model of aging, display many features that are known to occur early in the pathogenesis of AD such as increased oxidative stress, amyloid-β alterations, and tau phosphorylation. Therefore, SAMP8 mice may be an excellent model for studying the earliest neurodegenerative changes associated with AD and provide a more encompassing picture of human disease, a syndrome triggered by a combination of age-related events. Here, the neurochemical, neuropathological, and behavioral alterations, characterized in SAMP8 mice are critically reviewed and discussed in relation to the potential use of this mouse model in the study of AD pathogenesis.

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that causes progressive paralysis and death due to degeneration of motoneurons in spinal cord, brainstem and motor cortex. Nowadays, there is no effective therapy and patients die 2-5 years after diagnosis. Resveratrol (trans-3,4′,5-trihydroxystilbene) is a natural polyphenol found in grapes, with promising neuroprotective effects since it induces expression and activation of several neuroprotective pathways involving Sirtuin1 and AMPK. The objective of this work was to assess the effect of resveratrol administration on SOD1 G93A ALS mice. We determined the onset of symptoms by rotarod test and evaluated upper and lower motoneuron function using electrophysiological tests.We assessed the survival of the animals and determined the number of spinal motoneurons. Finally, we further investigated resveratrol mechanism of action by means of western blot and immunohistochemical analysis. Resveratrol treatment from 8 weeks of age significantly delayed disease onset and preserved lower and upper motoneuron function in female and male animals. Moreover, resveratrol significantly extended SOD1 G93A mice lifespan and promoted survival of spinal motoneurons. Delayed resveratrol administration from 12 weeks of age also improved spinal motoneuron function preservation and survival. Further experiments revealed that resveratrol protective effects were associated with increased expression and activation of Sirtuin 1 and AMPK in the ventral spinal cord. Both mediators promoted normalization of the autophagic flux and, more importantly, increased mitochondrial biogenesis in the SOD1 G93A spinal cord. Taken together, our findings suggest that resveratrol may represent a promising therapy for ALS.

Background Advancements in gerontology have revealed key insights into the molecular and biochemical aspects of the aging process. The sirtuin pathway, most notable for its association with the anti-aging effects of calorie restriction, has received particular attention, and pharmacologic or transgenic upregulation of the sirtuin pathway has demonstrated some very promising results in laboratory models of aging. Alzheimer disease (AD), the leading cause of senile dementia, is a devastating neurodegenerative condition that is imposing an increasing burden on society. The lack of therapeutics currently available for the disease provides strong incentive for the development of an effective treatment strategy and, interestingly, research has uncovered a novel mechanism of action of the sirtuin pathway that offers significant potential as such. Recent Developments Sirt1, one of the seven mammalian homologues of the sirtuin family of NAD+-dependent deacetylases, has recently been demonstrated to attenuate amyloidogenic processing of amyloid-β protein precursor (AβPP) in cell culture studies in vitro and transgenic mouse models of AD. Mechanistically, Sirt1 increases α-secretase production and activity through activation of the α-secretase gene ADAM10. Since α-secretase is the critical enzyme responsible for the non-amyloidogenic cleavage of AβPP, upregulation of α-secretase shifts AβPP processing to reduce the pathological accumulation of the presumptive toxic Aβ species that results from β- and γ-secretase activity. Interestingly, a recent study of the spatial patterns of Aβ deposition in the brain indicates a strong correlation with an increased utilization of aerobic glycolysis in those regions. Aerobic glycolysis depletes cellular levels of NAD+ (via decreased NAD+/NADH ratio), and it is possible that a corresponding downregulation of the NAD+-dependent sirtuin pathway is partly responsible for the amyloidogenic processing of AβPP. Where Next? The specific inhibition of Aβ generation by Sirt1 coupled with the link between aerobic glycolysis, NAD+ depletion, and amyloidogenesis via the sirtuin pathway has translational implications. On the one hand, the likely underlying role of the sirtuin pathway in AD onset and development may enlighten our understanding of this devastating condition. On the other, therapeutic upregulation of Sirt1 may provide opportunities for the amelioration of AD-type neuropathology through an inhibition of amyloidogenesis, among other things (i.e., regulation of cellular metabolism or inhibition of tau pathology — see below). Ultimately, further analysis into both aspects is necessary if any progress is to be made.

Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce β-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age.

A novel series of donepezil-tacrine hybrids designed to simultaneously interact with the active, peripheral and midgorge binding sites of acetylcholinesterase (AChE) have been synthesized and tested for their ability to inhibit AChE, butyrylcholinesterase (BChE), and AChE-induced A beta aggregation. These compounds consist of a unit of tacrine or 6-chlorotacrine, which occupies the same position as tacrine at the AChE active site, and the 5,6-dimethoxy-2-[(4-piperidinyl)methyl]-1-indanone moiety of donepezil (or the indane derivative thereof), whose position along the enzyme gorge and the peripheral site can be modulated by a suitable tether that connects tacrine and donepezil fragments. All of the new compounds are highly potent inhibitors of bovine and human AChE and BChE, exhibiting IC50 values in the subnanomolar or low nanomolar range in most cases. Moreover, six out of the eight hybrids of the series, particularly those bearing an indane moiety, exhibit a significant A beta antiaggregating activity, which makes them promising anti-Alzheimer drug candidates.

The consequences of the neurotoxic insult induced by 3,4-methylenedioxymethamphetamine (MDMA, an amphetamine derivative with specific action on the serotonergic system) were compared with those of methamphetamine (a derivative with specific action on dopaminergic system) in rats. Both drugs induced a very similar loss of body weight, especially evident 24 h after treatment. Their hyperthermic profile was also very similar and was dependent on ambient temperature, corroborating the thermo-dysregulatory effect of both substances. Methamphetamine (four injections of 10 mg kg(-1) s.c. at 2-h intervals) induced the loss of dopaminergic (35%) but not of serotonergic, terminals in the rat striatum and, simultaneously, a significant increase in striatal peripheral-type benzodiazepine receptor density, pointing to a glial reaction. Evidence for this drug-induced astrogliosis was the increased heat shock protein 27 (HSP27) expression in striatum, cortex and hippocampus. MDMA (20 mg kg(-1) s.c. b.i.d. for 4 days) induced a similar dopaminergic lesion in the striatum 3 days post-treatment, which reversed 4 days later. An important neurotoxic effect on serotonergic terminals was also observed in the cortex, striatum and hippocampus 3 days post-treatment, which partially reversed 4 days later in the striatum and hippocampus. No microglial activation was noticeable at either 3 or 7 days after MDMA treatment. This lack of effect on microglial cells was assessed by [(3)H]PK 11195 binding and OX-6 immunostaining, which were unchanged in the striatum and cortex after MDMA treatment. A non-significant tendency to increase was noted in the hippocampus 3 days after MDMA treatment. Furthermore, in MDMA-treated rats, neither HSP27 expression nor an increase in HSP27 immunoreactivity were detected. This result, together with the lack of increase in glial fibrilliary acidic protein (GFAP) immunoreactivity, indicate no astroglial activation at either 3 or 7 days post-treatment. Without microglial activation, an inflammatory process would not accompany the lesion induced by MDMA. The differences in glial activation between methamphetamine and MDMA observed in the present study could have implications for the prognosis of the injury induced by these drugs.