Healthy brain aging and delayed dementia in Texas rural elderly.

Healthy aging is the process of preserving and enhancing one's independence, physical and mental well-being, and overall quality of life. It involves the mental, emotional, and cognitive wellness. Although biological and genetic factors have a significant influence on the process of aging gracefully, other adjustable factors also play a crucial role. Adopting positive behaviors such as maintaining a nutritious and balanced diet, engaging in regular physical activity, effectively managing stress and anxiety, ensuring sufficient sleep, nurturing spiritual coping mechanisms, and prioritizing overall well-being from an early stage can collectively influence both lifespan and the quality of health during advanced years. We aim to explore the potential impacts of biological, psychosocial, and environmental factors on the process of healthy cognitive aging in individuals who exhibit healthy aging. Additionally, we plan to present initial findings that demonstrate how maintaining good cognitive health during aging could potentially postpone the emergence of neurodegenerative disorders. We hypothesize that there will be strong associations between biological, environmental, and social factors that cause some elderly to be superior in cognitive health than others. For preliminary data collection, we recruited 25 cognitively healthy individuals and 5 individuals with MCI/AD between the ages of 60-90 years. We conducted anthropometric measurements, and blood biomarker testing, administered surveys, and obtained structural brain magnetic resonance imaging (MRI) scans. The Montreal Cognitive Assessment (MoCA) scores and sub-scores for the healthy group were also reported. We found that at baseline, individuals exhibiting healthy cognitive aging, and those with MCI/AD had comparable measures of anthropometrics and blood biomarkers. The healthy group exhibited lower signs of brain volume loss and the ones observed were age-related. Moreover, within the healthy group, there was a significant correlation (p = 0.003) between age and MoCA scores. Conversely, within the individuals with MCI/AD, the MRI scans showed disease signs of grey and white matter and loss of cerebral volume. Healthy brain aging is a scientific area that remains under-explored. Our current study findings support our hypothesis. Future studies are required in diverse populations to determine the various biological, psychological, environmental, lifestyle, and social factors that contribute to it.

Impact of Chronic Conditions and Dementia in Rural West Texas: A Healthy Aging Study.

Alzheimer's disease (AD) is a devastating illness in elderly individuals, that currently has no known cure. Causal genetic factors only account for 1-2% of AD patients. However, other causal factors are still unknown for a majority of AD patients. Currently, multiple factors are implicated in late-onset AD, including unhealthy diet, physical inactivity, traumatic brain injury, chronic conditions, epigenetic factors, and environmental exposures. Although clinical symptoms of dementia are common to all races and ethnic groups, conditions that lead to dementia are different in terms of lifestyle, genetic profile, and socio-economic conditions. Increasing evidence also suggests that some elderly individuals age without cognitive impairments in their 60-90s as seen in rural West Texas, while some individuals progress with chronic conditions and cognitive impairments into their 60s. To understand these discriminations, we assessed current literature on demographic features of health in rural West Texas. This paper also outlines our initiated clinical study with a purpose of understanding the factors that allow some individuals to live without cognitive impairments at the age of 60-90 years, whereas others develop deficits in cognitive function around or above 60 years. Our ongoing study hopes to determine the factors that delay aging in some individuals by investigating various aspects including genetics, epigenetics, ethnicity, biology, culture, and lifestyle. This will be achieved by gathering information about participants' ethnographic profiles, cognitive assessments, blood-profiles, brain scans, and blood-based genomic analyses in relation to lifestyle. The outcomes of our study will provide insights into healthy aging in rural West Texas.

A partial reduction of Drp1 improves cognitive behavior and enhances mitophagy, autophagy and dendritic spines in a transgenic Tau mouse model of Alzheimer disease.

The purpose of our study is to understand the impact of a partial dynamin-related protein 1 (Drp1) on cognitive behavior, mitophagy, autophagy and mitochondrial and synaptic activities in transgenic Tau mice in Alzheimer's disease (AD). Our laboratory reported increased levels of amyloid-beta (Aß) and phosphorylated Tau (P-Tau) and reported that abnormal interactions between Aß and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and reduced fusion and synaptic activities in AD. These abnormal interactions result in the proliferation of dysfunctional mitochondria in AD neurons. Recent research on mitochondria revealed that fission protein Drp1 is largely implicated in mitochondrial dynamics in AD. To determine the impact of reduced Drp1 in AD, we recently crossed transgenic Tau mice with Drp1 heterozygote knockout (Drp1+/-) mice and generated double mutant (P301LDrp1+/-) mice. In the current study, we assessed the cognitive behavior, mRNA and protein levels of mitophagy, autophagy, mitochondrial biogenesis, dynamics and synaptic genes, mitochondrial morphology and mitochondrial function and dendritic spines in Tau mice relative to double mutant mice. When compared with Tau mice, double mutant mice did better on the Morris Maze (reduced latency to find hidden platform, increased swimming speed and time spent on quadrant) and rotarod (stayed a longer period of time) tests. Both mRNA- and protein-level autophagy, mitophagy, mitochondrial biogenesis and synaptic proteins were increased in double mutant mice compared with Tau (P301L) mice. Dendritic spines were significantly increased; mitochondrial number was reduced and length was increased in double mutant mice. Based on these observations, we conclude that reduced Drp1 is beneficial in a symptomatic-transgenic Tau (P301L) mice.

Protective effects of mitophagy enhancers against amyloid beta-induced mitochondrial and synaptic toxicities in Alzheimer disease.

The purpose of our study is to determine the protective effects of mitophagy enhancers against mutant APP and amyloid beta (Aß)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (ad). Over two decades of research from our lab and others revealed that mitochondrial abnormalities are largely involved in the pathogenesis of both early-onset and late-onset ad. Emerging studies from our lab and others revealed that impaired clearance of dead or dying mitochondria is an early event in the disease process. Based on these changes, it has been proposed that mitophagy enhancers are potential therapeutic candidates to treat patients with ad. In the current study, we optimized doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. We transfected HT22 cells with mutant APP cDNA and treated with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial dynamics, biogenesis, mitophagy and synaptic genes, cell survival; assessed mitochondrial respiration in mAPP-HT22 cells treated and untreated with mitophagy enhancers. We also assessed mitochondrial morphology in mAPP-HT22 cells treated and untreated with mitophagy enhancers. Mutant APP-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration, and excessively fragmented and reduced length of mitochondria. However, these events were reversed in mitophagy-enhancers-treated mutant mAPP-HT22 cells. Cell survival was significantly increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, mitochondrial number is reduced, and mitochondrial length is increased, and mitochondrial fragmentation is reduced in mitophagy-enhancers-treated mutant APP-HT22 cells. Further, urolithin A showed strongest protective effects against mutant APP and Aß-induced mitochondrial and synaptic toxicities in ad. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with ad.

MicroRNA-455-3p improves synaptic, cognitive functions and extends lifespan: Relevance to Alzheimer's disease.

BACKGROUND: MicroRNA-455-3p is one of the highly conserved miRNAs involved in multiple cellular functions in humans and we explored its relevance to learning and memory functions in Alzheimer's disease (AD). Our recent in vitro studies exhibited the protective role of miR-455-3p against AD toxicities in reducing full-length APP and amyloid-ß (Aß) levels, and also in reducing defective mitochondrial biogenesis, impaired mitochondrial dynamics and synaptic deficiencies. In the current study, we sought to determine the function of miR-455-3p in mouse models. METHODS: For the first time we generated both transgenic (TG) and knockout (KO) mouse models of miR-455-3p. We determined the lifespan extension, cognitive function, mitochondrial biogenesis, mitochondrial dynamics, mitochondrial morphology, dendritic spine density, synapse numbers and synaptic activity in miR-455-3p TG and KO mice. RESULTS: MiR-455-3p TG mice lived 5 months longer than wild-type (WT) counterparts, whereas KO mice lived 4 months shorter than WT mice. Morris water maze test showed improved cognitive behavior, spatial learning and memory in miR-455-3p TG mice relative to age-matched WT mice and miR-455-3p KO mice. Further, mitochondrial biogenesis, dynamics and synaptic activities were enhanced in miR-455-3p TG mice, while these were reduced in KO mice. Overall, overexpressed miR-455-3p in mice displayed protective effects, whereas depleted miR-455-3p in mice exhibited deleterious effects in relation to lifespan, cognitive behavior, and mitochondrial and synaptic activities. CONCLUSION: Both mouse models could be ideal research tools to understand the molecular basis of aging and its relevance to AD and other age-related diseases.

RALBP1 in Oxidative Stress and Mitochondrial Dysfunction in Alzheimer's Disease.

The purpose of our study is to understand the role of the RALBP1 gene in oxidative stress (OS), mitochondrial dysfunction and cognition in Alzheimer's disease (AD) pathogenesis. The RALPB1 gene encodes the 76 kDa protein RLIP76 (Rlip). Rlip functions as a stress-responsive/protective transporter of glutathione conjugates (GS-E) and xenobiotic toxins. We hypothesized that Rlip may play an important role in maintaining cognitive function. The aim of this study is to determine whether Rlip deficiency in mice is associated with AD-like cognitive and mitochondrial dysfunction. Brain tissue obtained from cohorts of wildtype (WT) and Rlip+/- mice were analyzed for OS markers, expression of genes that regulate mitochondrial fission/fusion, and synaptic integrity. We also examined mitochondrial ultrastructure in brains obtained from these mice and further analyzed the impact of Rlip deficiency on gene networks of AD, aging, stress response, mitochondrial function, and CREB signaling. Our studies revealed a significant increase in the levels of OS markers and alterations in the expression of genes and proteins involved in mitochondrial biogenesis, dynamics and synapses in brain tissues from these mice. Furthermore, we compared the cognitive function of WT and Rlip+/- mice. Behavioral, basic motor and sensory function tests in Rlip+/- mice revealed cognitive decline, similar to AD. Gene network analysis indicated dysregulation of stress-activated gene expression, mitochondrial function and CREB signaling genes in the Rlip+/- mouse brain. Our results suggest that Rlip deficiency-associated increases in OS and mitochondrial dysfunction could contribute to the development or progression of OS-related AD processes.

Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease.

The purpose of our study is to determine the protective effects of mitophagy enhancers against phosphorylated tau (P-tau)-induced mitochondrial and synaptic toxicities in Alzheimer's disease (AD). Mitochondrial abnormalities, including defective mitochondrial dynamics, biogenesis, axonal transport and impaired clearance of dead mitochondria are linked to P-tau in AD. Mitophagy enhancers are potential therapeutic candidates to clear dead mitochondria and improve synaptic and cognitive functions in AD. We recently optimized the doses of mitophagy enhancers urolithin A, actinonin, tomatidine, nicotinamide riboside in immortalized mouse primary hippocampal (HT22) neurons. In the current study, we treated mutant Tau expressed in HT22 (mTau-HT22) cells with mitophagy enhancers and assessed mRNA and protein levels of mitochondrial/synaptic genes, cell survival and mitochondrial respiration. We also assessed mitochondrial morphology in mTau-HT22 cells treated and untreated with mitophagy enhancers. Mutant Tau-HT22 cells showed increased fission, decreased fusion, synaptic & mitophagy genes, reduced cell survival and defective mitochondrial respiration. However, these events were reversed in mitophagy enhancers treated mTau-HT22 cells. Cell survival was increased, mRNA and protein levels of mitochondrial fusion, synaptic and mitophagy genes were increased, and mitochondrial fragmentation is reduced in mitophagy enhancers treated mTau-HT22 cells. Further, urolithin A showed strongest protective effects among all enhancers tested in AD. Our combination treatments of urolithin A + EGCG, addition to urolithin A and EGCG individual treatment revealed that combination treatments approach is even stronger than urolithin A treatment. Based on these findings, we cautiously propose that mitophagy enhancers are promising therapeutic drugs to treat mitophagy in patients with AD.

Mitochondrial Abnormalities and Synaptic Damage in Huntington's Disease: a Focus on Defective Mitophagy and Mitochondria-Targeted Therapeutics.

Huntington's disease (HD) is a fatal and pure genetic disease with a progressive loss of medium spiny neurons (MSN). HD is caused by expanded polyglutamine repeats in the exon 1 of HD gene. Clinically, HD is characterized by chorea, seizures, involuntary movements, dystonia, cognitive decline, intellectual impairment, and emotional disturbances. Several years of intense research revealed that multiple cellular changes, including defective axonal transport, protein-protein interactions, defective bioenergetics, calcium dyshomeostasis, NMDAR activation, synaptic damage, mitochondrial abnormalities, and selective loss of medium spiny neurons are implicated in HD. Recent research on mutant huntingtin (mHtt) and mitochondria has found that mHtt interacts with the mitochondrial division protein, dynamin-related protein 1 (DRP1), enhances GTPase DRP1 enzymatic activity, and causes excessive mitochondrial fragmentation and abnormal distribution, leading to defective axonal transport of mitochondria and selective synaptic degeneration. Recent research also revealed that failure to remove dead and/or dying mitochondria is an early event in the disease progression. Currently, efforts are being made to reduce abnormal protein interactions and enhance synaptic mitophagy as therapeutic strategies for HD. The purpose of this article is to discuss recent research in HD progression. This article also discusses recent developments of cell and mouse models, cellular changes, mitochondrial abnormalities, DNA damage, bioenergetics, oxidative stress, mitophagy, and therapeutics strategies in HD.

Defective mitophagy and synaptic degeneration in Alzheimer's disease: Focus on aging, mitochondria and synapse.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and multiple cognitive impairments. AD is marked by multiple cellular changes, including deregulation of microRNAs, activation of glia and astrocytes, hormonal imbalance, defective mitophagy, synaptic degeneration, in addition to extracellular neuritic amyloid-beta (Aß) plaques, phosphorylated tau (P-tau), and intracellular neurofibrillary tangles (NFTs). Recent research in AD revealed that defective synaptic mitophagy leads to synaptic degeneration and cognitive dysfunction in AD neurons. Our critical analyses of mitochondria and Aß and P-tau revealed that increased levels of Aß and P-Tau, and abnormal interactions between Aß and Drp1, P-Tau and Drp1 induced increased mitochondrial fragmentation and proliferation of dysfunctional mitochondria in AD neurons and depleted Parkin and PINK1 levels. These events ultimately lead to impaired clearance of dead and/or dying mitochondria in AD neurons. The purpose of our article is to highlight the recent research on mitochondria and synapses in relation to Aß and P-tau, focusing on recent developments.

Selective serotonin reuptake inhibitor citalopram ameliorates cognitive decline and protects against amyloid beta-induced mitochondrial dynamics, biogenesis, autophagy, mitophagy and synaptic toxicities in a mouse model of Alzheimer's disease.

In the current study, we investigated the protective role of citalopram against cognitive decline, impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective autophagy, mitophagy and synaptic dysfunction in APP transgenic mouse model of Alzheimer's disease (ad). We treated 12-month-old wild-type (WT) and age-matched transgenic APP mice with citalopram for 2 months. Using Morris Water Maze and rotarod tests, quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed cognitive behavior, RNA and protein levels of mitochondrial dynamics, biogenesis, autophagy, mitophagy, synaptic, ad-related and neurogenesis genes in wild-type and APP mice treated and untreated with citalopram. Citalopram-treated APP mice relative to citalopram-untreated APP mice exhibited improved cognitive behavior. Increased levels of mRNA associated with mitochondrial fission and ad-related genes; decreased levels of fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes were found in APP mice relative to WT mice. However, APP mice treated with citalopram compared to citalopram-untreated APP mice revealed reduced levels of the mitochondrial fission and ad-related genes and increased fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes. Our protein data agree with the mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice; these were reversed in citalopram-treated APP mice. Further, Golgi-cox staining analysis revealed reduced dendritic spines in APP mice relative to WT mice. However, citalopram-treated APP mice showed significantly increased dendritic spines, indicating that citalopram enhances spine density, synaptic activity and improved cognitive function in APP mice. These findings suggest that citalopram reduces cognitive decline, Aß levels and mitochondrial and synaptic toxicities and may have a strong protective role against mutant APP and Aß-induced injuries in patients with depression, anxiety and ad.