Alzheimer’s and Parkinson’s diseases are the two most common forms of neurodegenerative diseases. The exact etiology of these disorders is not well known; however, environmental, molecular, and genetic influences play a major role in the pathogenesis of these diseases. Using Alzheimer’s disease (AD) as the archetype, the pathological findings include the aggregation of Amyloid Beta (Aβ) peptides, mitochondrial dysfunction, synaptic degradation caused by inflammation, elevated reactive oxygen species (ROS), and cerebrovascular dysregulation. This review highlights the neuroinflammatory and neuroprotective role of epigallocatechin-3-gallate (EGCG): the medicinal component of green tea, a known nutraceutical that has shown promise in modulating AD progression due to its antioxidant, anti-inflammatory, and anti-aging abilities. This report also re-examines the current literature and provides innovative approaches for EGCG to be used as a preventive measure to alleviate AD and other neurodegenerative disorders.

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Epigallocatechin-3-Gallate (EGCG): New Therapeutic Perspectives for Neuroprotection, Aging, and Neuroinflammation for the Modern Age

Distinct grey matter volume alterations in adult patients with panic disorder and social anxiety disorder: A systematic review and voxel-based morphometry meta-analysis

Targeting whole body metabolism and mitochondrial bioenergetics in the drug development for Alzheimer's disease

Abstract Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer’s disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer’s disease neuropathology may uncover novel therapeutic targets to treat Alzheimer’s disease. It is well established that there are sex differences in response to Alzheimer’s disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20–25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15–44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, β (females) = 0.08, P (females) = 5.76 × 10−09, β (males) = −0.01, P(males) = 0.70, β (interaction) = 0.09, P (interaction) = 1.01 × 10−04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer’s disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer’s disease may be personalized based on their biological sex and genetic context.

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Sex differences in the genetic architecture of cognitive resilience to Alzheimer’s disease

Dysregulated glutamate signaling, leading to neuronal excitotoxicity and death, has been associated with neurodegenerative pathologies. 17β-estradiol (E2) is a human steroid hormone having a role in reproduction, sexual maturation, brain health and biological activities. The study aimed to explain the neuroprotective role of E2 against glutamate-induced ROS production, MAP kinase-dependent neuroinflammation, synaptic dysfunction and neurodegeneration in the cortex and hippocampus of postnatal day 7 rat brain. Biochemical and immunofluorescence analyses were applied. Our results showed that a single subcutaneous injection of glutamate (10 mg/kg) induced brain oxidative stress after 4 h by disturbing the homeostasis of glutathione (GSH) and revealed an upsurge in ROS and LPO levels and downregulated the expression of Nrf2 and HO-1 antioxidant protein. The glutamate-exposed P7 pups illustrated increased phosphorylation of stress-activated c-Jun N-terminal kinase (JNK) and p38 kinase (p38) and downregulated expression of P-Erk1/2. This was accompanied by pathological neuroinflammation as revealed by enhanced gliosis with upregulated expression of GFAP and Iba-1, and the activation of proinflammatory cytokines (TNF-α) in glutamate-injected P7 pups. Moreover, exogenous glutamate also reduced the expression of synaptic markers (PSD-95, SYP) and induced apoptotic neurodegeneration in the cortical and hippocampal regions by dysregulating the expression of Bax, Bcl-2 and caspase-3 in the developing rat brain. On the contrary, co-treatment of E2 (10 mg/kg) with glutamate significantly abrogated brain neuroinflammation, neurodegeneration and synapse loss by alleviating brain oxidative stress by upregulating the Nrf2/HO-1 antioxidant pathway and by deactivating pro-apoptotic P-JNK/P-p38 and activation of pro-survival P-Erk1/2 MAP kinase pathways. In brief, the data demonstrate the neuroprotective role of E2 against glutamate excitotoxicity-induced neurodegeneration. The study also encourages future studies investigating if E2 may be a potent neuroprotective and neurotherapeutic agent in different neurodegenerative diseases.

17-β Estradiol Rescued Immature Rat Brain against Glutamate-Induced Oxidative Stress and Neurodegeneration via Regulating Nrf2/HO-1 and MAP-Kinase Signaling Pathway.

Chloe Lopez-Lee

Papers

Sex Differences in Neurodegeneration: The Role of the Immune System in Humans.