Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of cytokines and an exacerbated inflammatory response to pathological changes. Whereas LPS increases nitric oxide (NO) secretion in microglia from young mice, induction of reactive oxygen species (ROS) predominates in older mice. Furthermore, there is accumulation of DNA oxidative damage in mitochondria of microglia during aging, and also an increased intracellular ROS production. Increased ROS activates the redox-sensitive nuclear factor kappa B, which promotes more neuroinflammation, and can be translated in functional deficits, such as cognitive impairment. Mitochondria-derived ROS and cathepsin B, are also necessary for the microglial cell production of interleukin-1 beta, a key inflammatory cytokine. Interestingly, whereas the regulatory cytokine TGF beta 1 is also increased in the aged brain, neuroinflammation persists. Assessing this apparent contradiction, we have reported that TGF beta 1 induction and activation of Smad3 signaling after inflammatory stimulation are reduced in adult mice. Other protective functions, such as phagocytosis, although observed in aged animals, become not inducible by inflammatory stimuli and TGF beta 1. Here, we discuss data suggesting that mitochondrial and endolysosomal dysfunction could at least partially mediate age-associated microglial cell changes, and, together with the impairment of the TGF beta 1-Smad3 pathway, could result in the reduction of protective activation and the facilitation of cytotoxic activation of microglia, resulting in the promotion of neurodegenerative diseases.
Omega-3 polyunsaturated fatty acids (PUFAs) exhibit neuroprotective properties and represent a potential treatment for a variety of neurodegenerative and neurological disorders. However, traditionally there has been a lack of discrimination between the different omega -3 PUFAs and effects have been broadly accredited to the series as a whole. Evidence for unique effects of eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA) and more recently docosapentaenoic acid (DPA) is growing. For example, beneficial effects in mood disorders have more consistently been reported in clinical trials using EPA; whereas, with neurodegenerative conditions such as Alzheimer's disease, the focus has been on DHA. DHA is quantitatively the most important omega-3 PUFA in the brain, and consequently the most studied, whereas the availability of high purity DPA preparations has been extremely limited until recently, limiting research into its effects. However, there is now a growing body of evidence indicating both independent and shared effects of EPA, DPA and DHA. The purpose of this review is to highlight how a detailed understanding of these effects is essential to improving understanding of their therapeutic potential. The review begins with an overview of omega -3 PUFA biochemistry and metabolism, with particular focus on the central nervous system (CNS), where DHA has unique and indispensable roles in neuronal membranes with levels preserved by multiple mechanisms. This is followed by a review of the different enzymederived anti-inflammatory mediators produced from EPA, DPA and DHA. Lastly, the relative protective effects of EPA, DPA and DHA in normal brain aging and the most common neurodegenerative disorders are discussed. With a greater understanding of the individual roles of EPA, DPA and DHA in brain health and repair it is hoped that appropriate dietary recommendations can be established and therapeutic interventions can be more targeted and refined.
Hearing loss with increasing age adversely affects the ability to understand speech, an effect that results partly from reduced audibility. The aims of this study were to establish whether aging reduces speech intelligibility for listeners with normal audiograms, and, if so, to assess the relative contributions of auditory temporal and cognitive processing. Twenty-one older normal-hearing (ONH; 60-79 years) participants with bilateral audiometric thresholds <= 20 dB HL at 0.125-6 kHz were matched to nine young (YNH; 18-27 years) participants in terms of mean audiograms, years of education, and performance IQ. Measures included: (1) identification of consonants in quiet and in noise that was unmodulated or modulated at 5 or 80 Hz; (2) identification of sentences in quiet and in co-located or spatially separated two-talker babble; (3) detection of modulation of the temporal envelope (TE) at frequencies 5-180 Hz; (4) monaural and binaural sensitivity to temporal fine structure (TFS); (5) various cognitive tests. Speech identification was worse for ONH than YNH participants in all types of background. This deficit was not reflected in self-ratings of hearing ability. Modulation masking release (the improvement in speech identification obtained by amplitude modulating a noise background) and spatial masking release (the benefit obtained from spatially separating masker and target speech) were not affected by age. Sensitivity to TE and TES was lower for ONH than YNH participants, and was correlated positively with speech-in-noise (SiN) identification. Many cognitive abilities were lower for ONH than YNH participants, and generally were correlated positively with SiN identification scores. The best predictors of the intelligibility of SiN were composite measures of cognition and TES sensitivity. These results suggest that declines in speech perception in older persons are partly caused by cognitive and perceptual changes separate from age-related changes in audiometric sensitivity.
Research has shown the human brain is organized into separable functional networks during rest and varied states of cognition, and that aging is associated with specific network dysfunctions. The present study used functional magnetic resonance imaging (fMRI) to examine low-frequency (0.008 < f < 0.08 Hz) coherence of cognitively relevant and sensory brain networks in older adults who participated in a 1-year intervention trial, comparing the effects of aerobic and non-aerobic fitness training on brain function and cognition. Results showed that aerobic training improved the aging brain's resting functional efficiency in higher-level cognitive networks. One year of walking increased functional connectivity between aspects of the frontal, posterior, and temporal cortices within the Default Mode Network and a Frontal Executive Network, two brain networks central to brain dysfunction in aging. Length of training was also an important factor. Effects in favor of the walking group were observed only after 12 months of training, compared to non-significant trends after 6 months. A non-aerobic stretching and toning group also showed increased functional connectivity in the DMN after 6 months and in a Frontal Parietal Network after 12 months, possibly reflecting experience-dependent plasticity. Finally, we found that changes in functional connectivity were behaviorally relevant. Increased functional connectivity was associated with greater improvement in executive function. Therefore the study provides the first evidence for exercise-induced functional plasticity in large-scale brain systems in the aging brain, using functional connectivity techniques, and offers new insight into the role of aerobic fitness in attenuating age-related brain dysfunction.
Oxidative stress (OS), caused by the imbalance between the generation and detoxification of reactive oxygen and nitrogen species (ROS/RNS), plays an important role in brain aging, neurodegenerative diseases, and other related adverse conditions, such as ischemia. While ROS/RNS serve as signaling molecules at physiological levels, an excessive amount of these molecules leads to oxidative modification and, therefore, dysfunction of proteins, nucleic acids, and lipids. The response of neurons to this pervasive stress, however, is not uniform in the brain. While many brain neurons can cope with a rise in OS, there are select populations of neurons in the brain that are vulnerable. Because of their selective vulnerability, these neurons are usually the first to exhibit functional decline and cell death during normal aging, or in age-associated neurodegenerative diseases, such as Alzheimer's disease. Understanding the molecular and cellular mechanisms of selective neuronal vulnerability (SNV) to OS is important in the development of future intervention approaches to protect such vulnerable neurons from the stresses of the aging process and the pathological states that lead to neurodegeneration. In this review, the currently known molecular and cellular factors that contribute to SNV to OS are summarized. Included among the major underlying factors are high intrinsic OS, high demand for ROS/RNS-based signaling, low ATP production, mitochondrial dysfunction, and high inflammatory response in vulnerable neurons. The contribution to the selective vulnerability of neurons to OS by other intrinsic or extrinsic factors, such as deficient DNA damage repair, low calcium-buffering capacity, and glutamate excitotoxicity, are also discussed.
Glial cells have a variety of functions in the brain, ranging from immune defense against external and endogenous hazardous stimuli, regulation of synaptic formation, calcium homeostasis, and metabolic support for neurons. Their dysregulation can contribute to the development of neurodegenerative disorders, including Alzheimer's disease (AD). One of the most important functions of glial cells in AD is the regulation of Amyloid-beta (A beta) levels in the brain. Microglia and astrocytes have been reported to play a central role as moderators of A beta clearance and degradation. The mechanisms of A beta degradation by glial cells include the production of proteases, including neprilysin, the insulin degrading enzyme, and the endothelin-converting enzymes, able to hydrolyse A beta at different cleavage sites. Besides these enzymes, other proteases have been described to have some role in A beta elimination, such as plasminogen activators, angiotensin-converting enzyme, and matrix metalloproteinases. Other relevant mediators that are released by glial cells are extracellular chaperones, involved in the clearance of A beta alone or in association with receptors/transporters that facilitate their exit to the blood circulation. These include apolipoproteins, alpha 2macroglobulin, and alpha 1-antichymotrypsin. Finally, astrocytes and microglia have an essential role in phagocytosing A beta, in many cases via a number of receptors that are expressed on their surface. In this review, we examine all of these mechanisms, providing an update on the latest research in this field.
In animal models, the incretin hormone GLP-1 affects Alzheimer's disease (AD). We hypothesized that treatment with GLP-1 or an analog of GLP-1 would prevent accumulation of AI) and raise, or prevent decline of, glucose metabolism (CMRglc) in AD. In this 26-week trial, we randomized 38 patients with AD to treatment with the GLP1 analog liraglutide (n = 18), or placebo (n = 20). We measured A beta load in brain with tracer [11 C]PIB (P1B), CMRglc with [F-18]FDG (FDG), and cognition with the WMS-IV scale (ClinicalTrials.gov NCT01469351). The PIB binding increased significantly in temporal lobe in placebo and treatment patients (both P = 0.04), and in occipital lobe in treatment patients (P = 0.04). Regional and global increases of PIB retention did not differ between the groups (P >= 0.38). In placebo treated patients CMRglc declined in all regions, significantly so by the following means in precuneus (P = 0.009, 3.2 mu mol/hg/min, 95% CI: 5.45; 0.92), and in parietal (P = 0.04, 2.1 mu mol/hg/min, 95% CI: 4.21; 0.081), temporal (P = 0.046, 1.54 mu mol/hg/min, 95% CI: 3.05; 0.030), and occipital (P = 0.009, 2.10 mu mol/hg/min, 95% CI: 3.61; 0.59) lobes, and in cerebellum (P = 0.04, 1.54 mu mol/hg/min, 95% CI: 3.01; 0.064). In contrast, the GLP-1 analog treatment caused a numerical but insignificant increase of CMR(gl)c after 6 months. Cognitive scores did not change. We conclude that the GLP-1 analog treatment prevented the decline of CMRgic that signifies cognitive impairment, synaptic dysfunction, and disease evolution. We draw no firm conclusions from the A beta load or cognition measures, for which the study was underpowered.
Iron is the most abundant transition metal within the brain, and is vital for a number of cellular processes including neurotransmitter synthesis, myelination of neurons, and mitochondrial function. Redox cycling between ferrous and ferric iron is utilized in biology for various electron transfer reactions essential to life, yet this same chemistry mediates deleterious reactions with oxygen that induce oxidative stress. Consequently, there is a precise and tightly controlled mechanism to regulate iron in the brain. When iron is dysregulated, both conditions of iron overload and iron deficiencies are harmful to the brain. This review focuses on how iron metabolism is maintained in the brain, and how an alteration to iron and iron metabolism adversely affects neurological function.
We examined whether positive transfer of cognitive training, which so far has been observed for individual tests only, also generalizes to cognitive abilities, thereby carrying greater promise for improving everyday intellectual competence in adulthood and old age. In the COGITO Study, 101 younger and 103 older adults practiced six tests of perceptual speed (PS), three tests of working memory (WM), and three tests of episodic memory (EM) for over 100 daily 1-h sessions. Transfer assessment included multiple tests of PS, WM, EM, and reasoning. In both age groups, reliable positive transfer was found not only for individual tests but also for cognitive abilities, represented as latent factors. Furthermore, the pattern of correlations between latent change factors of practiced and latent change factors of transfer tasks indicates systematic relations at the level of broad abilities, making the interpretation of effects as resulting from unspecific increases in motivation or self-concept less likely.
The incidence of dementia is increasing at an alarming rate, and has become a major public health concern. Alzheimer disease (AD) is the most common form of dementia and is characterized by progressive cognitive impairment. In addition to classical neuropathological features such as amyloid plagues and neurofibrillary tangles (NET), accumulation of activated immune cells has been documented in the AD brain, suggesting a contribution of neuroinflammation in the pathogenesis of AD. Besides cognitive deterioration, non cognitive symptoms, such as agitation, aggression, depression and psychosis, are often observed in demented patients, including those with AD, and these neuropsychological symptoms place a heavy burden on caregivers. These symptoms often exhibit sudden onset and tend to fluctuate over time, and in many cases, they are triggered by an infection in peripheral organs, suggesting that inflammation plays an important role in the pathogenesis of these non-cognitive symptoms. However, there is no mechanistic explanation for the relationship between inflammation and neuropsychiatric symptoms. Observations from experimental mouse models indicate that alteration of brain blood vessels, especially blood brain barrier (BBB) dysfunction, may contribute to the relationship. The current review summarizes the results from recent studies on the relationship between inflammation and AD, while focusing on cerebrovascular alterations, which might provide an insight into the pathogenesis of cognitive/non-cognitive symptoms in AD patients and suggest a basis for the development of new therapeutic treatments for these conditions.
Vascular cognitive impairment (VCI) [vascular cognitive disorder (VCD), vascular dementia] describes a continuum of cognitive disorders ranging from mild cognitive impairment (MCI) to dementia, in which vascular brain injury involving regions important for memory, cognition and behavior plays an important role. Clinical diagnostic criteria show moderate sensitivity (ca 50%) and variable specificity (range 64-98%). In Western clinical series, VaD is suggested in 8-10% of cognitively impaired elderly subjects. Its prevalence in autopsy series varies from 0.03 to 58%, with means of 8 to 15% (in Japan 22-35%). Major types of sporadic VaD are multi-infarct encephalopathy, small vessel and strategic infarct type dementias, subcortical areteriosclerotic leukoencephalopathy (SAE) (Binswanger), multilacunar state, mixed cortico-subcrotical type, granular cortical atrophy (rare), postischemic encephalopathy, and a mixture of cerebrovascular lesions (CVLs). They result from systemic, cardiac and local large or small vessel disease (SVD); their pathogenesis is multifactorial. Hereditary forms of VaD caused by gene mutations are rare Cognitive decline is commonly associated with widespread small ischemic vascular lesions involving subcortical brain areas (basal ganglia and hemispherical white matter). The lesions affect neuronal networks involved in cognition, memory, and behavior (thalamo-cortical, striato-subfrontal, cortico-subcortical, limbic systems). CVLs often coexist with Alzheimer-type lesions and other pathologies; 25-80% of elderly demented show mixed pathologies. The lesion pattern of "pure" VaD differs from that in mixed dementia (AD + CVLs) suggesting different pathogenesis of both phenotypes. Minor CVLs, except for severe amyloid angiopathy, appear not essential for cognitive impairment in full-blown AD, while both mild AD-type pathology and SVD may interact synergistically in promoting dementia. However, in a large percentage of non-demented elderly individuals, both AD-related and vascular brain pathologies have been reported. Despite recent suggestions for staging and grading CVLs in specific brain areas, due to the high variability of CVLs associated with cognitive impairment, no validated neuropathological criteria are currently available for VaD and mixed dementia. Further clinico-pathological studies and harmonization of neuropathological procedures are needed to validate the diagnostic criteria for VaD and mixed dementia in order to clarify the impact of CVLs and other coexistent pathologies on cognitive impairment as a basis for further successful therapeutic options.
Amyotrophic lateral sclerosis (ALS) is a devastating condition with an estimated mortality of 30,000 patients a year worldwide. The median reported survival time since onset ranges from 24 to 48 months. Riluzole is the only currently approved mildly efficacious treatment. Riluzole received marketing authorization in 1995 in the USA and in 1996 in Europe. In the years that followed, over 60 molecules have been investigated as a possible treatment for ALS. Despite significant research efforts, the overwhelming majority of human clinical trials (CTs) have failed to demonstrate clinical efficacy. In the past year, oral masitinib and intravenous edaravone have emerged as promising new therapeutics with claimed efficacy in CTs in ALS patients. Given their advanced phase of clinical development one may consider these drugs as the most likely near-term additions to the therapeutic arsenal available for patients with ALS. In terms of patient inclusion, CT with masitinib recruited a wider, more representative, less restrictive patient population in comparison to the only successful edaravone CT (edaravone eligibility criteria represents only 18% of masitinib study patients). The present manuscript reviews >50 CTs conducted in the last 20 years since riluzole was first approved. A special emphasis is put on the analysis of existing evidence in support of the clinical efficacy of edaravone and masitinib and the possible implications of an eventual marketing authorisation in the treatment of ALS.
Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (A beta) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of alpha-synuclein (alpha-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of A beta, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in relation to protein aggregates and degenerated neurons. The activated microglia can release pro-inflammatory cytokines which can aggravate and propagate neuroinflammation, thereby degenerating neurons and impairing brain as well as retinal function. The aim of the present review is to describe the contribution in retina to microglial-mediated neuroinflammation in AD, PD, and glaucomatous neurodegeneration.
Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging.
Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind, and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n = 30 in each group) treating with either milk (control group) or a mixture of probiotics (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus Bifidobacterium bifidum, and Lactobacillus fermenturn (2 x 10(9) CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (-5.03% +/- 3.00), the probiotic treated (+27.90% +/- 8.07) patients showed a significant improvement in the MMSE score (P 0.001). In addition, changes in plasma malondialdehyde (-22.01% +/- 4.84 vs. +2.67% +/- 3.86 mu mol/L, P 0.001), serum high-sensitivity C-reactive protein (-17.61% +/- 3.70 vs. +45.26% +/- 3.50 mu g/mL, P 0.001), homeostasis model of assessment estimated insulin resistance (+28.84% +/- 13.34 vs. +76.95% +/- 24.60, P = 0.002), Beta cell function (+3.45% +/- 10.91 vs. +75.62% +/- 23.18, P = 0.001), serum triglycerides (-20.29% +/- 4.49 vs. 0.16% +/- 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity check index (-1.83 +/- 1.26 vs. 4.66 +/- 1.70, P = 0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current study demonstrated that probiotic consumption for 12 weeks positively affects cognitive function and some metabolic statuses in the AD patients.
Aging is associated with a progressive loss of muscle mass and strength and a decline in neurophysiological functions. Age-related neuromuscular junction (NMJ) plays a key role in musculoskeletal impairment that occurs with aging. However, whether changes in the NMJ precede or follow the decline of muscle mass and strength remains unresolved. Many factors such as mitochondrial dysfunction, oxidative stress, inflammation, changes in the innervation of muscle fibers, and mechanical properties of the motor units probably perform an important role in NMJ degeneration and muscle mass and strength decline in late life. This review addresses the primary events that might lead to NMJ dysfunction with aging, including studies on biomarkers, signaling pathways, and animal models. Interventions such as caloric restriction and exercise may positively affect the NMJ through this mechanism and attenuate the age-related progressive impairment in motor function.
There is growing consensus that intervention and treatment of Huntington disease (HD) should occur at the earliest stage possible. Various early-intervention methods for this fatal neurodegenerative disease have been identified, but preventive clinical trials for HD are limited by a lack of knowledge of the natural history of the disease and a dearth of appropriate outcome measures. Objectives of the current study are to document the natural history of premanifest HD progression in the largest cohort ever studied and to develop a battery of imaging and clinical markers of premanifest HD progression that can be used as outcome measures in preventive clinical trials. Neurobiological predictors of Huntington's disease is a 32-site, international, observations study of premanifest HD, with annual examination of 1013 participants with premanifest HD and 301 gene-expansion negative controls between 2001 and 2012. Findings document 39 variables representing imaging, motor, cognitive, functional, and psychiatric domains, showing different rates of decline between premanifest HD and controls. Required sample size and models of premanifest HD are presented to inform future design of clinical and preclinical research. Preventive clinical trials in premanifest HD with participants who have a medium or high probability of motor onset are calculated to be as resource-effective as those conducted in diagnosed HD and could interrupt disease 7-12 years earlier. Methods and measures for preventive clinical trials in premanifest HD more than a dozen years from motor onset are also feasible. These findings represent the most thorough documentation of a clinical battery for experimental therapeutics in stages of premanifest HD, the time period for which effective intervention may provide the most positive possible outcome for patients and their families affected by this devastating disease.
Caloric restriction (CR), fasting, and exercise have long been recognized for their neuroprotective and lifespan-extending properties; however, the underlying mechanisms of these phenomen are main elusive. Such extraordinary benefits might be linked to the activation of sirtuins. In mammals, the sirtuin family has seven members (SIRT1-7), which diverge in tissue distribution, subcellular localization, enzymatic activity, and targets. SIRT1, SIRT2, and SIRT3 have deacetylase activity. Their dependence on NAD(+) directly links their activity to the metabolic status of the cell. High NAD(+) levels convey neuroprotective effects, possibly via activation of sirtuin family members. Mitochondrial sirtuin3 (SIRT3) has received much attention for its role in metabolism and aging. Specific small nucleotide polymorphisms in Sirt3 are linked to increased human lifespan. SIRT3 mediates the adaptation of increased energy demand during CR, fasting, and exercise to increased production of energy equivalents. SIRT3 deacetylates and activates mitochondrial enzymes involved in fatty acid beta-oxidation, aminoacid metabolism, the electron transport chain, and antioxidant defenses. As a result, the mitochondrial energy metabolism increases. In addition, SIRT3 prevents apoptosis by lowering reactive oxygen species and inhibiting components of the mitochondrial permeability transition pore. Mitochondrial deficits associated with aging and neurodegeneration might therefore be slowed or even prevented by SIRT3 activation. In addition, upregulating SIRT3 activity by dietary supplementation of sirtuin activating compounds might promote the beneficial effects of this enzyme. The goal of this review is to summarize emerging data supporting an europrotective action of SIRT3 against Alzheimer'sdisease, Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
Alzheimer's disease is a chronic neurodegenerative disorder characterized by a progressive loss of cognitive and behavioral abilities. Extracellular senile plaques and intracellular neurofibrillary tangles are hallmarks of AD. Researchers aim to analyze the molecular mechanisms underlying AD pathogenesis; however, the therapeutic options available to treat this disease are inadequate. In the past few years, several studies have reported interesting insights about the neuroprotective properties of the polyphenolic compound resveratrol (3, 5, 4'-trihydroxy-trans-stilbene) when used with in vitro and in vivo models of AD. The aim of this review is to focus on the neuroprotective and antioxidant effects of resveratrol on AD and its multiple potential mechanisms of action. In addition, because the naturally occurring forms of resveratrol have a very limited half-life in plasma, a description of potential analogs aimed at increasing the bioavailability in plasma is also discussed.