{"title":"Prenatal and adolescent alcohol exposure, neuroinflammation, and Alzheimer’s disease: a network meta analysis approach","authors":"Lazer Gerlikhman, Ujjal Das, Dipak K. Sarkar","doi":"10.1515/nipt-2023-0003","DOIUrl":"https://doi.org/10.1515/nipt-2023-0003","url":null,"abstract":"Abstract Objectives This review aims to determine the connection between developmental alcohol exposure and its potential impact on Alzheimer's disease (AD) later in life. We employ a network meta-analysis approach and examine gene fold changes from literature and Gene Expression Omnibus (GEO) datasets. Our goal is to investigate whether prenatal alcohol exposure (PAE) and/or adolescent alcohol exposure (AAE) could activate specific neuroinflammatory genes, potentially increasing the risk of AD development. Content We conducted a comprehensive analysis of brain datasets using a network meta-analysis approach. By synthesizing gene fold changes from literature and GEO datasets, we examined the potential impact of developmental alcohol exposure on increased risk of developing AD in the future. Summary Our findings reveal significant associations between alcohol exposure and critical functional categories and diseases in the brain. Alcohol exposure was strongly linked to the “Inflammatory Response” and “Nervous System Development and Function” categories, indicative of inflammatory reactions in the brain and detrimental effects on nervous system integrity. Furthermore, we observed links with “Organismal Injury and Abnormalities” and “Cell Death and Survival.” Pathway analysis revealed dysregulation in neuroinflammatory, ERK/MAPK signaling, amyloid processing, IL-1 signaling and calcium signaling pathways, suggesting their potential involvement in alcohol-induced neurotoxicity. Outlook This review highlights the necessity of recognizing developmental alcohol exposure as a potential risk factor for AD and shed light on the underlying mechanisms that may contribute to alcohol-induced neurotoxicity. By expanding our understanding of these mechanisms, we can better address the complex relationship between developmental alcohol exposure and neurodegenerative disorders like AD.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43310333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mai M Abdelmoaty, Pravin Yeapuri, Jatin Machhi, Yaman Lu, Krista L Namminga, Rana Kadry, Eugene Lu, Shaurav Bhattarai, Rodney Lee Mosley, Howard E Gendelman
{"title":"Immune senescence in aged APP/PS1 mice.","authors":"Mai M Abdelmoaty, Pravin Yeapuri, Jatin Machhi, Yaman Lu, Krista L Namminga, Rana Kadry, Eugene Lu, Shaurav Bhattarai, Rodney Lee Mosley, Howard E Gendelman","doi":"10.1515/nipt-2023-0015","DOIUrl":"10.1515/nipt-2023-0015","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate the linkage between age and deficits in innate and adaptive immunity which heralds both Alzheimer's disease (AD) onset and progression. The pathobiological events which underlie and tie these outcomes remain not fully understood.</p><p><strong>Methods: </strong>To investigate age-dependent immunity in AD, we evaluated innate and adaptive immunity in coordinate studies of regulatory T cell (Treg) function, T cell frequencies, and microglial integrity. These were assessed in blood, peripheral lymphoid tissues, and the hippocampus of transgenic (Tg) amyloid precursor protein/presenilin 1 (APP/PS1) against non-Tg mice. Additionally, immune arrays of hippocampal tissue were performed at 4, 6, 12, and 20 months of age.</p><p><strong>Results: </strong>APP/PS1 mice showed progressive impairment of Treg immunosuppressive function with age. There was partial restoration of Treg function in 20-month-old mice. Ingenuity pathway analyses of hippocampal tissues were enriched in inflammatory, oxidative, and cellular activation pathways that paralleled advancing age and AD-pathobiology. Operative genes in those pathways included, but were not limited to triggering receptor on myeloid cells 1 (TREM1), T helper type 1 (Th1), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathways. Interleukin-17 (IL-17), nitric oxide, acute phase, and T cell receptor signaling pathways were also perturbed. Significant inflammation was observed at 6- and 12-months. However, at 20-months, age associated partial restoration of Treg function reduced inflammatory phenotype.</p><p><strong>Conclusions: </strong>Impaired Treg function, inflammation and oxidative stress were associated with AD pathology. Age associated partial restoration of Treg function in old mice reduced the hippocampal inflammatory phenotype. Restoring Treg suppressive function can be a therapeutic modality for AD.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":"317-330"},"PeriodicalIF":0.0,"publicationDate":"2023-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10659760/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46909718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sudipta Chakrabarti, Sukhamoy Gorai, Kalipada Pahan
{"title":"A simple protocol for isolating microglia from adult mouse brain.","authors":"Sudipta Chakrabarti, Sukhamoy Gorai, Kalipada Pahan","doi":"10.1515/nipt-2023-0014","DOIUrl":"10.1515/nipt-2023-0014","url":null,"abstract":"<p><strong>Objectives: </strong>Although microglia are activated in adult and aged brains resulting in neurodegenerative and neuroinflammatory disorders, most of the cell culture studies on microglia deal with neonatal microglia because of ease of isolation. Microglia could be isolated from adult brains, but it requires separation by density gradient centrifugation, magnetic beads, etc. Here, we describe a simple protocol of isolating highly purified microglia from adult mouse brains.</p><p><strong>Methods: </strong>Our protocol involves dilution with sterile PBS or media, regular centrifugation, and plating on poly-D-lysine-coated flasks.</p><p><strong>Results: </strong>These adult microglia expressed the inducible nitric oxide synthase in response to preformed α-syn fibril, an etiological reagent of Parkinson's disease, and bacterial lipopolysaccharides, one of the prototype proinflammatory stimuli. Moreover, these adult microglia exhibited phagocytosis, which was stimulated by LPS treatment.</p><p><strong>Conclusions: </strong>These results suggest that adult microglia isolated by our procedure are functional and that these adult microglia could be used for studies related to neurodegenerative disorders.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 1","pages":"293-300"},"PeriodicalIF":0.0,"publicationDate":"2023-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48987881","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ivy Antwi, Destiny Watkins, Alahn Pedawi, Atheel Ghrayeb, Christine Van de Vuurst, Theodore J Cory
{"title":"Substances of abuse and their effect on SAR-CoV-2 pathogenesis.","authors":"Ivy Antwi, Destiny Watkins, Alahn Pedawi, Atheel Ghrayeb, Christine Van de Vuurst, Theodore J Cory","doi":"10.1515/nipt-2023-0004","DOIUrl":"10.1515/nipt-2023-0004","url":null,"abstract":"<p><p>Following the emergence of SARS-CoV-2, various reports suggest that there has been a significant increase in substance abuse due to social distancing and related issues. Several reports have suggested the impact of chronic substance use on individuals' physiological and psychological health. Therefore, there is a need to know the impact of SARS-CoV-2 on persons with substance use disorders. Individuals with substance use disorders are the most vulnerable groups and are at a high risk of SARS-CoV-2 infection due to their already existing health issues associated with substance use. This review discusses some of the molecular and systemic/organic effects chronic substance use such as alcohol, nicotine, marijuana (cannabis), opioids, methamphetamine, and cocaine have on SARS-CoV-2 infectivity and its potential cause for worsened disease outcomes in persons with substance use disorder. This will provide healthcare providers, public health policies, and researchers with the needed knowledge to address some of the many challenges faced during the Covid-19 pandemic to facilitate treatment strategies for persons with substance use disorders.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 1","pages":"301-316"},"PeriodicalIF":0.0,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474379/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"47402015","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Natalie M Zahr, Edith V Sullivan, Adolf Pfefferbaum
{"title":"Poor subjective sleep reported by people living with HIV is associated with impaired working memory.","authors":"Natalie M Zahr, Edith V Sullivan, Adolf Pfefferbaum","doi":"10.1515/nipt-2023-0010","DOIUrl":"10.1515/nipt-2023-0010","url":null,"abstract":"<p><p>Poor sleep can undermine health and may be especially disruptive to those with chronic conditions including HIV infection. Here, clinically well-described people living with HIV [PLWH] (74 men, 35 women) and healthy control (38 men, 35 women) participants were administered the Pittsburgh Sleep Quality Index (PSQI), a validated measure of subjective sleep with a global score ≥5 able to distinguish good from poor sleepers. In addition, participants completed a battery of neuropsychological tests. PLWH (6.8 ± 3.7) had higher global PSQI scores than healthy controls (4.1 ± 2.8): 39.7 % of uninfected controls and 68.8 % of PLWH had a PSQI≥5 indicative of poor sleep. There were no relations between the global PSQI score and any evaluated variables among uninfected individuals or with demographic or HIV-related variables in PLWH. Instead, a higher global PSQI score among PLWH was associated with worse \"Quality of Life\" scores [Global Assessment of Functioning (GAF, p=0.0007), Medical Outcomes Study survey (21-item short form, SF-21, p<i><</i>0.0001), and Activities of Daily Living-Instrumental (ADL-I, p=0.0041)] and higher Beck Depression Index (BDI, p<i><</i>0.0001) depressive symptoms. Further, in PLWH, higher global PSQI scores were associated with poor performance on a working memory task, the digit backward span (p=0.0036). In PLWH, the 5 variables together explained 32.3 % of the global PSQI score variance; only 3 variables - the SF-21, BDI, and digit backward scores - explained 30.6 % of the variance. To the extent that poor subjective sleep contributes to impaired working memory in HIV, we speculate that this impairment may be ameliorated by improved sleep health.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 1","pages":"127-137"},"PeriodicalIF":0.0,"publicationDate":"2023-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10635409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46212192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pedro J Rodriguez Rivera, Huajun Liang, Amal Isaiah, Christine C Cloak, Miriam S Menken, Meghann C Ryan, Thomas Ernst, Linda Chang
{"title":"Prenatal tobacco exposure on brain morphometry partially mediated poor cognitive performance in preadolescent children.","authors":"Pedro J Rodriguez Rivera, Huajun Liang, Amal Isaiah, Christine C Cloak, Miriam S Menken, Meghann C Ryan, Thomas Ernst, Linda Chang","doi":"10.1515/nipt-2023-0013","DOIUrl":"10.1515/nipt-2023-0013","url":null,"abstract":"<p><strong>Objectives: </strong>To evaluate whether prenatal tobacco exposure (PTE) is related to poorer cognitive performance, abnormal brain morphometry, and whether poor cognitive performance is mediated by PTE-related structural brain differences.</p><p><strong>Methods: </strong>The Adolescent Brain Cognitive Development study dataset was used to compare structural MRI data and neurocognitive (NIH Toolbox<sup>®</sup>) scores in 9-to-10-year-old children with (n=620) and without PTE (n=10,989). We also evaluated whether PTE effects on brain morphometry mediated PTE effects on neurocognitive scores. Group effects were evaluated using Linear Mixed Models, covaried for socio-demographics and prenatal exposures to alcohol and/or marijuana, and corrected for multiple comparisons using the false-discovery rate (FDR).</p><p><strong>Results: </strong>Compared to unexposed children, those with PTE had poorer performance (all p-values <0.05) on executive function, working memory, episodic memory, reading decoding, crystallized intelligence, fluid intelligence and overall cognition. Exposed children also had thinner parahippocampal gyri, smaller surface areas in the posterior-cingulate and pericalcarine cortices; the lingual and inferior parietal gyri, and smaller thalamic volumes (all p-values <0.001). Furthermore, among children with PTE, girls had smaller surface areas in the superior-frontal (interaction-FDR-p=0.01), precuneus (interaction-FDR-p=0.03) and postcentral gyri (interaction-FDR-p=0.02), while boys had smaller putamen volumes (interaction-FDR-p=0.02). Smaller surface areas across regions of the frontal and parietal lobes, and lower thalamic volumes, partially mediated the associations between PTE and poorer neurocognitive scores (p-values <0.001).</p><p><strong>Conclusions: </strong>Our findings suggest PTE may lead to poorer cognitive performance and abnormal brain morphometry, with sex-specific effects in some brain regions, in pre-adolescent children. The poor cognition in children with PTE may result from the smaller areas and subcortical brain volumes.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":"375-386"},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"46661305","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Santosh Kumar, Namita Sinha, Sunitha Kodidela, Sandip Godse, Bhupesh Singla, Udai P Singh, Hari K Bhat
{"title":"Resveratrol and its analogs suppress HIV replication, oxidative stress, and inflammation in macrophages.","authors":"Santosh Kumar, Namita Sinha, Sunitha Kodidela, Sandip Godse, Bhupesh Singla, Udai P Singh, Hari K Bhat","doi":"10.1515/nipt-2023-0012","DOIUrl":"10.1515/nipt-2023-0012","url":null,"abstract":"<p><strong>Objectives: </strong>HIV suppression in brain viral reservoirs, especially macrophages, and microglia is critical to suppress HIV neuropathogenesis and subsequently HIV-associated neurocognitive disorders (HAND). Since most antiretroviral therapy (ART) drugs do not achieve optimal therapeutic concentrations in the brain and can cause neurotoxicity, an alternative/adjuvant therapy is needed to suppress HIV neuropathogenesis. In this study, our objectives were to examine the anti-HIV, antioxidant, and anti-inflammatory potential of resveratrol (RES) and its synthetic analogs 4-(E)-{(p-tolylimino)-methylbenzene-1,2-diol} (TIMBD) and 4-(E)-{(4-hydroxyphenylimino)-methylbenzene,1,2-diol} (HPIMBD) in HIV-infected macrophages.</p><p><strong>Methods: </strong>We used HIV replication (viral load), oxidative stress (reactive oxygen species and antioxidant enzymes), and inflammatory response (pro- and anti-inflammatory cytokines/chemokines) assays to achieve the objectives of the study.</p><p><strong>Results: </strong>Our results showed that RES and its analogs HPIMBD and TIMBD at 25 µM concentration significantly decrease HIV replication in both primary monocyte-derived macrophages and U1-differentiated macrophages. Moreover, RES and its analogs do not induce any cytotoxicity for up to 3 days in these cells. Further, treatment with RES and TIMBD (25 µM) also reduced the levels of reactive oxygen species without affecting the expression of antioxidant enzymes, SOD1, and catalase in U1 macrophages. Besides, RES and HPIMBD treatment inhibited the proinflammatory cytokines and chemokines in U1 macrophages, which was associated with decreased levels of anti-inflammatory cytokines. Importantly, our western blot experiments show that RES also decreases cellular proinflammatory cytokine IL-1β, which is usually elevated in both myeloid and neuronal cells upon HIV infection.</p><p><strong>Conclusions: </strong>Taken together, our results suggest that RES and/or its analogs are important adjuvants that may be used not only to suppress HIV but also oxidative stress and inflammation in brain viral reservoirs.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"0 1","pages":"365-374"},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696571/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"43147123","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Stacey L Piotrowski, Allison Tucker, Steven Jacobson
{"title":"The elusive role of herpesviruses in Alzheimer's disease: current evidence and future directions.","authors":"Stacey L Piotrowski, Allison Tucker, Steven Jacobson","doi":"10.1515/nipt-2023-0011","DOIUrl":"10.1515/nipt-2023-0011","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common cause of dementia. While pathologic hallmarks, such as extracellular beta-amyloid plaques, are well-characterized in affected individuals, the pathogenesis that causes plaque formation and eventual cognitive decline is not well understood. A recent resurgence of the decades-old \"infectious hypothesis\" has garnered increased attention on the potential role that microbes may play in AD. In this theory, it is thought that pathogens such as viruses may act as seeds for beta-amyloid aggregation, ultimately leading to plaques. Interest in the infectious hypothesis has also spurred further investigation into additional characteristics of viral infection that may play a role in AD progression, such as neuroinflammation, latency, and viral DNA integration. While a flurry of research in this area has been recently published, with herpesviruses being of particular interest, the role of pathogens in AD remains controversial. In this review, the insights gained thus far into the possible role of herpesviruses in AD are summarized. The challenges and potential future directions of herpesvirus research in AD and dementia are also discussed.</p>","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":"2 1","pages":"253-266"},"PeriodicalIF":0.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10474380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41377612","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Janvhi S. Machhar, Elias Abou-Jaoude, S. Schwartz, R. Aalinkeel, S. Mahajan
{"title":"NLRP3 inflammasome activation underlies the neuro-oxidative stress associated with Methamphetamine (METH) and SARS-CoV2 induced co-morbidity in human microglia","authors":"Janvhi S. Machhar, Elias Abou-Jaoude, S. Schwartz, R. Aalinkeel, S. Mahajan","doi":"10.1515/nipt-2023-0005","DOIUrl":"https://doi.org/10.1515/nipt-2023-0005","url":null,"abstract":"Abstract Acute and chronic use of Methamphetamine (METH) has critical immunological implications and METH users are more vulnerable to SARS-CoV2 infection. Inflammasomes are activated in response to SARS-CoV2 infection. METH also activates NLRP3 inflammasome in microglia and promotes neuro cognitive deficits. The goal of the study was to examine the involvement of NLRP3 inflammasome in METH and/or SARS-CoV2 induced neuro-oxidative stress in microglial cells. Our results suggests that METH +/− SARS-CoV2 initiated a neuro immune-inflammatory response and mitochondrial oxidative stress via NLRP3 inflammasome activation induced increased Caspase −1 and increased lipid peroxidation. Our data suggests that SARS-CoV2 infection in METH abusing subjects may result in long-term neurological deficits resulting from microglial dysfunction and apoptosis attributed to NLRP3 inflammasome activation.","PeriodicalId":74278,"journal":{"name":"NeuroImmune pharmacology and therapeutics","volume":" ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"45564754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}