The Latest Articles on Ageing and Neurodegenerative Diseases

Our staff editors continue to share exciting, engaging, and thought-provoking reading material in the recommended articles series.

This week, we would like to share several of the latest articles on Ageing and Neurodegenerative Diseases.

Title: Phytochemicals targeting nitric oxide signaling in neurodegenerative diseases
Authors: Tapan Behl, Tarapati Rana, Aayush Sehgal, Hafiz A. Makeen, Mohammed Albratty, Hassan A. Alhazmi, Abdulkarim M. Meraya, Saurabh Bhatia, Monika Sachdeva
Type: Review Article
Abstract:
Neurodegenerative diseases are a set of diseases in which slow and progressive neuronal loss occurs. Nitric oxide (NO) as a neurotransmitter performs key roles in the stimulation and blockade of various inflammatory processes. Although physiological NO is necessary for protection against a variety of pathogens, reactive oxygen species-mediated oxidative stress induces inflammatory cascades and apoptosis. Activation of glial cells particularly astrocytes and microglia induce overproduction of NO, resulting in neuroinflammation and neurodegenerative disorders. Hence, inhibiting the overproduction of NO is a beneficial therapeutic approach for numerous neuroinflammatory conditions. Several compounds have been explored for the management of neurodegenerative disorders, but they have minor symptomatic benefits and several adverse effects. Phytochemicals have currently gained more consideration owing to their ability to reduce the overproduction of NO in neurodegenerative disorders. Furthermore, phytochemicals are generally considered to be safe and beneficial. The mechanisms of NO generation and their implications in neurodegenerative disorders are explored in this review article, as well as several newly discovered phytochemicals that might have NO inhibitory activity. The current review could aid in the discovery of new anti-neuroinflammatory drugs that can suppress NO generation, particularly during neuroinflammatory and neurodegenerative conditions.
Access this article: https://doi.org/10.1016/j.niox.2022.11.001

Title: The D-serine biosynthetic enzyme serine racemase is expressed by reactive astrocytes in the amygdala of human and a mouse model of Alzheimer's disease
Authors: Oluwarotimi O. Folorunso, Theresa L. Harvey, Stephanie E. Brown, Gabriele Chelini, Sabina Berretta, Darrick T. Balu
Type: Research Article
Abstract:
Alzheimer's disease (AD) is characterized behaviorally by cognitive deterioration and emotional disruption, and neuropathologically by amyloid-β (A β) plaques, neurofibrillary tangles, and complement C3 (C3)-expressing neurotoxic, reactive astrocytes. We previously demonstrated that C3 + reactive astrocytes in the hippocampus and entorhinal cortex of AD patients express serine racemase (SR), which produces the N-methyl-D-aspartate receptor (NMDAR) co-agonist D-serine. We show here that C3 + reactive astrocytes express SR in the amygdala of AD patients and in an amyloid mouse model of familial AD (5xFAD). 5xFAD mice also have deficits in cue fear memory recall that is dependent on intact amygdala function. Our results suggest that D-serine produced by reactive astrocytes in the amygdala could contribute to glutamate excitotoxicity and neurodegeneration observed with AD progression.
Access this article: https://doi.org/10.1016/j.neulet.2022.136958

Title: Plasmalogens inhibit neuroinflammation and promote cognitive function
Authors: Md Shamim Hossain, Shiro Mawatari, Takehiko Fujino
Type: Review Article
Abstract:
Neuroinflammation (NF) is defined as the activation of brain glial cells that are found in neurodegenerative diseases including Alzheimer’s disease (AD). It has been known that an increase in NF could reduce the memory process in the brain but the key factors, associated with NF, behind the dysregulation of memory remained elusive. We previously reported that the NF and aging processes reduced the special phospholipids, plasmalogens (Pls), in the murine brain by a mechanism dependent on the activation of transcription factors, NF-kB and c-MYC. A similar mechanism has also been found in postmortem human brain tissues with AD pathologies and in the AD model mice. Recent evidence showed that these phospholipids enhanced memory and reduced neuro-inflammation in the murine brain. Pls can stimulate the cellular signaling molecules, ERK and Akt, by activating the membrane-bound G protein-coupled receptors (GPCRs). Therefore, recent findings suggest that plasmalogens could be one of the key phospholipids in the brain to enhance memory and inhibit NF.
Access this article: https://doi.org/10.1016/j.brainresbull.2022.11.005

Title: Surface-modified lipid nanocarriers for crossing the blood-brain barrier (BBB): A current overview of active targeting in brain diseases
Authors: Maria Inês Teixeira, Carla M. Lopes, Maria Helena Amaral, Paulo C. Costa
Type: Review Article
Abstract:
The blood-brain barrier (BBB) restricts the access of therapeutic agents to the brain, complicating the treatment of neurological diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), glioma, etc. To overcome this limitation and improve drug delivery to the central nervous system (CNS), the potential of nanocarriers, including lipid-based nanosystems, has been explored. Through active targeting, the surface of the nanocarriers can be modified with ligands that interact with the BBB, enhancing their uptake and penetration across the brain endothelium by different physiological mechanisms, such as receptor- or transporter-mediated transcytosis. This review seeks to provide an overview of active targeting in brain delivery, while highlighting the potential of functionalized lipid nanocarriers to treat brain diseases. Therefore, in the first sections, we discuss the importance of active targeting in CNS drug delivery, present the different ligands commonly used for functionalization, as well as summarize the state of the art of the most recent and relevant studies of surface-modified lipid nanosystems developed for neurological disorders. Lastly, challenges hindering clinical translation are discussed, and critical insights and future perspectives outlined. Although some limitations have been identified, it is expected that in the upcoming years these nanosystems will be an established approach.
Access this article: https://doi.org/10.1016/j.colsurfb.2022.112999

Title: Caloric restriction reinforces the stem cell pool in the aged brain without affecting overall proliferation status
Authors: Begun Erbaba, Duygu Macaroglu, N. Ilgim Ardic-Avci, Ayca Arslan-Ergul, Michelle M. Adams
Type: Research Article
Abstract:
Overfeeding (OF) and obesity increase the risk for brain aging and neurodegenerative diseases due to increased oxidative stress and neuroinflammation, which likely contribute to cellular dysfunction. In contrast, caloric restriction (CR) is an intervention known for its effects on extending both life- and health-span. In the current study, the effects on the aging brain of two short-term feeding regimens, OF and CR, were investigated. We applied these diets for 12 weeks to both young and aged zebrafish. We performed protein and mRNA level analysis to examine diet-mediated effects on any potential age-related alterations in the brain. Markers implicated in the regulation of brain aging, cell cycle, proliferation, inflammation, and cytoskeleton were analyzed. The most prominent result observed was a downregulation in the expression levels of the stem cell marker, Sox2, in CR-fed animals as compared to OF-fed fish. Furthermore, our data highlighted significant age-related downregulations in Tp53, Myca, and L-plastin levels. The multivariate analyses of all datasets suggested that as opposed to OF, the adaptive mechanisms increasing lifespan via CR are likely exerting their effects by reinforcing the stem cell pool and downregulating inflammation. The data reveal important therapeutic targets with respect to the state of nutrient uptake for the slowing down of the detrimental effects of aging, resulting in a healthy and extended lifespan, as well as lowering the risk for neurodegenerative disease.
Access this article: https://doi.org/10.1016/j.gene.2022.147026