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Mitochondria in Alzheimer's Disease Pathogenesis

Reiss, Allison B; Gulkarov, Shelly; Jacob, Benna; Srivastava, Ankita; Pinkhasov, Aaron; Gomolin, Irving H; Stecker, Mark M; Wisniewski, Thomas; De Leon, Joshua
Alzheimer's disease (AD) is a progressive and incurable neurodegenerative disorder that primarily affects persons aged 65 years and above. It causes dementia with memory loss and deterioration in thinking and language skills. AD is characterized by specific pathology resulting from the accumulation in the brain of extracellular plaques of amyloid-β and intracellular tangles of phosphorylated tau. The importance of mitochondrial dysfunction in AD pathogenesis, while previously underrecognized, is now more and more appreciated. Mitochondria are an essential organelle involved in cellular bioenergetics and signaling pathways. Mitochondrial processes crucial for synaptic activity such as mitophagy, mitochondrial trafficking, mitochondrial fission, and mitochondrial fusion are dysregulated in the AD brain. Excess fission and fragmentation yield mitochondria with low energy production. Reduced glucose metabolism is also observed in the AD brain with a hypometabolic state, particularly in the temporo-parietal brain regions. This review addresses the multiple ways in which abnormal mitochondrial structure and function contribute to AD. Disruption of the electron transport chain and ATP production are particularly neurotoxic because brain cells have disproportionately high energy demands. In addition, oxidative stress, which is extremely damaging to nerve cells, rises dramatically with mitochondrial dyshomeostasis. Restoring mitochondrial health may be a viable approach to AD treatment.
PMID: 38398707
ISSN: 2075-1729
CID: 5634602

Cholesterol deficiency as a mechanism for autism: A valproic acid model

Peltier, Morgan R; Behbodikhah, Jennifer; Renna, Heather A; Ahmed, Saba; Srivastava, Ankita; Arita, Yuko; Kasselman, Lora J; Pinkhasov, Aaron; Wisniewski, Thomas; De Leon, Joshua; Reiss, Allison B
Dysregulated cholesterol metabolism represents an increasingly recognized feature of autism spectrum disorder (ASD). Children with fetal valproate syndrome caused by prenatal exposure to valproic acid (VPA), an anti-epileptic and mood-stabilizing drug, have a higher incidence of developing ASD. However, the role of VPA in cholesterol homeostasis in neurons and microglial cells remains unclear. Therefore, we examined the effect of VPA exposure on regulation of cholesterol homeostasis in the human microglial clone 3 (HMC3) cell line and the human neuroblastoma cell line SH-SY5Y. HMC3 and SH-SY5Y cells were each incubated in increasing concentrations of VPA, followed by quantification of mRNA and protein expression of cholesterol transporters and cholesterol metabolizing enzymes. Cholesterol efflux was evaluated using colorimetric assays. We found that VPA treatment in HMC3 cells significantly reduced ABCA1 mRNA, but increased ABCG1 and CD36 mRNA levels in a dose-dependent manner. However, ABCA1 and ABCG1 protein levels were reduced by VPA in HMC3. Furthermore, similar experiments in SH-SY5Y cells showed increased mRNA levels for ABCA1, ABCG1, CD36, and 27-hydroxylase with VPA treatment. VPA exposure significantly reduced protein levels of ABCA1 in a dose-dependent manner, but increased the ABCG1 protein level at the highest dose in SH-SY5Y cells. In addition, VPA treatment significantly increased cholesterol efflux in SH-SY5Y, but had no impact on efflux in HMC3. VPA differentially controls the expression of ABCA1 and ABCG1, but regulation at the transcriptional and translational levels are not consistent and changes in the expression of these genes do not correlate with cholesterol efflux in vitro.
PMID: 37864505
ISSN: 1708-8267
CID: 5612952

Androgen Deprivation Therapy for Prostate Cancer: Focus on Cognitive Function and Mood

Reiss, Allison B; Gulkarov, Shelly; Pinkhasov, Aaron; Sheehan, Katie M; Srivastava, Ankita; De Leon, Joshua; Katz, Aaron E
Prostate cancer is the second leading cause of cancer death in men in the United States. Androgen deprivation therapy (ADT) is currently the primary treatment for metastatic prostate cancer, and some studies have shown that the use of anti-androgen drugs is related to a reduction in cognitive function, mood changes, diminished quality of life, dementia, and possibly Alzheimer's disease. ADT has potential physiological effects such as a reduction in white matter integrity and a negative impact on hypothalamic functions due to the lowering of testosterone levels or the blockade of downstream androgen receptor signaling by first- and second-generation anti-androgen drugs. A comparative analysis of prostate cancer patients undergoing ADT and Alzheimer patients identified over 30 shared genes, illustrating common ground for the mechanistic underpinning of the symptomatology. The purpose of this review was to investigate the effects of ADT on cognitive function, mood, and quality of life, as well as to analyze the relationship between ADT and Alzheimer's disease. The evaluation of prostate cancer patient cognitive ability via neurocognitive testing is described. Future studies should further explore the connection among cognitive deficits, mood disturbances, and the physiological changes that occur when hormonal balance is altered.
PMID: 38256338
ISSN: 1648-9144
CID: 5624802

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer's Disease

Srivastava, Ankita; Johnson, Maryann; Renna, Heather A; Sheehan, Katie M; Ahmed, Saba; Palaia, Thomas; Pinkhasov, Aaron; Gomolin, Irving H; De Leon, Joshua; Reiss, Allison B
Mitochondrial degeneration in various neurodegenerative diseases, specifically in Alzheimer's disease, involves excessive mitochondrial fission and reduced fusion, leading to cell damage. P110 is a seven-amino acid peptide that restores mitochondrial dynamics by acting as an inhibitor of mitochondrial fission. However, the role of P110 as a neuroprotective agent in AD remains unclear. Therefore, we performed cell culture studies to evaluate the neuroprotective effect of P110 on amyloid-β accumulation and mitochondrial functioning. Human SH-SY5Y neuronal cells were incubated with 1 µM and 10 µM of P110, and Real-Time PCR and Western blot analysis were done to quantify the expression of genes pertaining to AD and neuronal health. Exposure of SH-SY5Y cells to P110 significantly increased APP mRNA levels at 1 µM, while BACE1 mRNA levels were increased at both 1 µM and 10 µM. However, protein levels of both APP and BACE1 were significantly reduced at 10 µM of P110. Further, P110 treatment significantly increased ADAM10 and Klotho protein levels at 10 µM. In addition, P110 exposure significantly increased active mitochondria and reduced ROS in live SH-SY5Y cells at both 1 µM and 10 µM concentrations. Taken together, our results indicate that P110 might be useful in attenuating amyloid-β generation and improving neuronal health by maintaining mitochondrial function in neurons.
PMID: 38004296
ISSN: 2075-1729
CID: 5609092

Maximizing the Clinical Value of Blood-Based Biomarkers for Mild Traumatic Brain Injury

Rauchman, Steven H; Pinkhasov, Aaron; Gulkarov, Shelly; Placantonakis, Dimitris G; De Leon, Joshua; Reiss, Allison B
Mild traumatic brain injury (TBI) and concussion can have serious consequences that develop over time with unpredictable levels of recovery. Millions of concussions occur yearly, and a substantial number result in lingering symptoms, loss of productivity, and lower quality of life. The diagnosis may not be made for multiple reasons, including due to patient hesitancy to undergo neuroimaging and inability of imaging to detect minimal damage. Biomarkers could fill this gap, but the time needed to send blood to a laboratory for analysis made this impractical until point-of-care measurement became available. A handheld blood test is now on the market for diagnosis of concussion based on the specific blood biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin carboxyl terminal hydrolase L1 (UCH-L1). This paper discusses rapid blood biomarker assessment for mild TBI and its implications in improving prediction of TBI course, avoiding repeated head trauma, and its potential role in assessing new therapeutic options. Although we focus on the Abbott i-STAT TBI plasma test because it is the first to be FDA-cleared, our discussion applies to any comparable test systems that may become available in the future. The difficulties in changing emergency department protocols to include new technology are addressed.
PMID: 37958226
ISSN: 2075-4418
CID: 5611112

Amyloid-β Effects on Peripheral Nerve: A New Model System

Stecker, Mark M; Srivastava, Ankita; Reiss, Allison B
Although there are many biochemical methods to measure amyloid-β (Aβ)42 concentration, one of the critical issues in the study of the effects of Aβ42 on the nervous system is a simple physiological measurement. The in vitro rat sciatic nerve model is employed and the nerve action potential (NAP) is quantified with different stimuli while exposed to different concentrations of Aβ42. Aβ42 predominantly reduces the NAP amplitude with minimal effects on other parameters except at low stimulus currents and short inter-stimulus intervals. The effects of Aβ42 are significantly concentration-dependent, with a maximum reduction in NAP amplitude at a concentration of 70 nM and smaller effects on the NAP amplitude at higher and lower concentrations. However, even physiologic concentrations in the range of 70 pM did reduce the NAP amplitude. The effects of Aβ42 became maximal 5-8 h after exposure and did not reverse during a 30 min washout period. The in vitro rat sciatic nerve model is sensitive to the effects of physiologic concentrations of Aβ42. These experiments suggest that the effect of Aβ42 is a very complex function of concentration that may be the result of amyloid-related changes in membrane properties or sodium channels.
PMID: 37833938
ISSN: 1422-0067
CID: 5604442

Alzheimer's Disease Treatment: The Search for a Breakthrough

Reiss, Allison B; Muhieddine, Dalia; Jacob, Berlin; Mesbah, Michael; Pinkhasov, Aaron; Gomolin, Irving H; Stecker, Mark M; Wisniewski, Thomas; De Leon, Joshua
As the search for modalities to cure Alzheimer's disease (AD) has made slow progress, research has now turned to innovative pathways involving neural and peripheral inflammation and neuro-regeneration. Widely used AD treatments provide only symptomatic relief without changing the disease course. The recently FDA-approved anti-amyloid drugs, aducanumab and lecanemab, have demonstrated unclear real-world efficacy with a substantial side effect profile. Interest is growing in targeting the early stages of AD before irreversible pathologic changes so that cognitive function and neuronal viability can be preserved. Neuroinflammation is a fundamental feature of AD that involves complex relationships among cerebral immune cells and pro-inflammatory cytokines, which could be altered pharmacologically by AD therapy. Here, we provide an overview of the manipulations attempted in pre-clinical experiments. These include inhibition of microglial receptors, attenuation of inflammation and enhancement of toxin-clearing autophagy. In addition, modulation of the microbiome-brain-gut axis, dietary changes, and increased mental and physical exercise are under evaluation as ways to optimize brain health. As the scientific and medical communities work together, new solutions may be on the horizon to slow or halt AD progression.
PMID: 37374288
ISSN: 1648-9144
CID: 5538642

Toxic External Exposure Leading to Ocular Surface Injury

Rauchman, Steven H; Locke, Brandon; Albert, Jacqueline; De Leon, Joshua; Peltier, Morgan R; Reiss, Allison B
The surface of the eye is directly exposed to the external environment, protected only by a thin tear film, and may therefore be damaged by contact with ambient particulate matter, liquids, aerosols, or vapors. In the workplace or home, the eye is subject to accidental or incidental exposure to cleaning products and pesticides. Organic matter may enter the eye and cause infection. Ocular surface damage can trigger a range of symptoms such as itch, discharge, hyperemia, photophobia, blurred vision, and foreign body sensation. Toxin exposure can be assessed clinically in multiple ways, including via measurement of tear production, slit-lamp examination, corneal staining, and conjunctival staining. At the cellular level, environmental toxins can cause oxidative damage, apoptosis of corneal and conjunctival cells, cell senescence, and impaired motility. Outcomes range from transient and reversible with complete healing to severe and sight-compromising structural changes. Classically, evaluation of tolerance and safety was carried out using live animal testing; however, new in vitro and computer-based, in silico modes are superseding the gold standard Draize test. This review examines how environmental features such as pollutants, temperature, and seasonality affect the ocular surface. Chemical burns to the eye are considered, and approaches to protect the ocular surface are detailed.
PMID: 37092465
ISSN: 2411-5150
CID: 5464992

Exosomes in Cardiovascular Disease: From Mechanism to Therapeutic Target

Reiss, Allison B; Ahmed, Saba; Johnson, Maryann; Saeedullah, Usman; De Leon, Joshua
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality globally. In recent decades, clinical research has made significant advances, resulting in improved survival and recovery rates for patients with CVD. Despite this progress, there is substantial residual CVD risk and an unmet need for better treatment. The complex and multifaceted pathophysiological mechanisms underlying the development of CVD pose a challenge for researchers seeking effective therapeutic interventions. Consequently, exosomes have emerged as a new focus for CVD research because their role as intercellular communicators gives them the potential to act as noninvasive diagnostic biomarkers and therapeutic nanocarriers. In the heart and vasculature, cell types such as cardiomyocytes, endothelial cells, vascular smooth muscle, cardiac fibroblasts, inflammatory cells, and resident stem cells are involved in cardiac homeostasis via the release of exosomes. Exosomes encapsulate cell-type specific miRNAs, and this miRNA content fluctuates in response to the pathophysiological setting of the heart, indicating that the pathways affected by these differentially expressed miRNAs may be targets for new treatments. This review discusses a number of miRNAs and the evidence that supports their clinical relevance in CVD. The latest technologies in applying exosomal vesicles as cargo delivery vehicles for gene therapy, tissue regeneration, and cell repair are described.
PMID: 37110138
ISSN: 2218-1989
CID: 5465492

A Rare Single Case of COVID-19-Induced Acute Myocarditis and Encephalopathy Presenting Simultaneously

Saeedullah, Usman; Abbas, Anas M.; Ward, Caitlin; Bayya, Maha; Bhandari, Jenish; Abbas, Araf M.; DeLeon, Joshua; Reiss, Allison B.
The ongoing coronavirus disease 2019 (COVID-19) pandemic may result in cardiovascular complications such as myocarditis, while encephalitis is a potentially life-threatening COVID-19-associated central nervous system complication. This case illustrates the possibility of developing severe multisystem symptoms from a COVID-19 infection, despite having received the COVID-19 vaccine within the year. Delay in treatment for myocarditis and encephalopathy can lead to permanent and possibly fatal damage. Our patient, a middle-aged female with a complicated medical history, initially came in without characteristic manifestations of myocarditis such as shortness of breath, chest pain, or arrhythmia, but with an altered mental status. Through further laboratory tests, the patient was diagnosed with myocarditis and encephalopathy, which were resolved within weeks through medical management and physical/occupational therapy. This case presentation describes the first reported case of concomitant COVID-19 myocarditis and encephalitis after receiving a booster dose within the year.
ISSN: 2076-393x
CID: 5460472