Infection and Immunometabolism in the Central Nervous System: A Possible Mechanistic Link Between Metabolic Imbalance and Dementia

Abstract

Metabolic syndromes are frequently associated with dementia, suggesting that the dysregulation of energy metabolism can increase the risk of neurodegeneration and cognitive impairment. In addition, growing evidence suggests the link between infections and brain disorders, including Alzheimer’s disease. The immune system and energy metabolism are in an intricate relationship. Infection triggers immune responses, which are accompanied by imbalance in cellular and organismal energy metabolism, while metabolic disorders can lead to immune dysregulation and higher infection susceptibility. In the brain, the activities of brain-resident immune cells, including microglia, are associated with their metabolic signatures, which may be affected by central nervous system (CNS) infection. Conversely, metabolic dysregulation can compromise innate immunity in the brain, leading to enhanced CNS infection susceptibility. Thus, infection and metabolic imbalance can be intertwined to each other in the etiology of brain disorders, including dementia. Insulin and leptin play pivotal roles in the regulation of immunometabolism in the CNS and periphery, and dysfunction of these signaling pathways are associated with cognitive impairment. Meanwhile, infectious complications are often comorbid with diabetes and obesity, which are characterized by insulin resistance and leptin signaling deficiency. Examples include human immunodeficiency virus (HIV) infection and periodontal disease caused by an oral pathogen Porphyromonas gingivalis. This review explores potential interactions between infectious agents and insulin and leptin signaling pathways, and discuss possible mechanisms underlying the relationship between infection, metabolic dysregulation, and brain disorders, particularly focusing on the roles of insulin and leptin.

Insulin and Memory in Invertebrates

“…It is important to note that learning ability depends on the state of starvation in invertebrates. Short-term fasting in mammals also enhances cognition, including memory consolidation (Dias et al, 2021 ), whereas obesity impairs cognition and increases the risk of dementia in humans (Shinjyo and Kita, 2021 ). Extensive studies using invertebrates can provide important insight into the advantages of short-term fasting in humans.…”

Berberine: A Promising Treatment for Neurodegenerative Diseases

“…Alzheimer’s disease, an age-related neurodegenerative disease, affects the quality of life of patients, and their families. Patient with Alzheimer’s disease suffer from memory loss, cognitive decline, energy metabolism dysregulation, changes in personality, and behavior ( Goedert and Spillantini, 2006 ; Ribeiro et al, 2017 ; Shinjyo and Kita, 2021 ). Although a considerable new research progress has been made in Alzheimer’s disease research, the pathogenesis remains unclear.…”

An exploratory pilot study on the involvement of APOE, HFE, C9ORF72 variants and comorbidities in neurocognitive and physical performance in a group of HIV-infected people

“…Despite of efficient ART, the prevalence of neurocognitive deficits in PWH, collectively termed HIV-associated neurocognitive disorders (HAND), remains high and HIV-1 infection is associated with up to 40–50% of patients with HAND although, thanks to ART, HAND currently presents with milder symptoms (mild/moderate cognitive decline or MCD). The neuropathogenesis of HAND is now believed to be largely the result of neurocognitive and/or motor decline, driven by chronic brain inflammation (Hong and Banks 2015 ; Farhadian et al 2017 ; Shinjyo and Kita 2021 ; Borrajo et al 2021 ). It is well-known that some HIV proteins can activate macrophages, astrocytes and microglial cells in the brain, leading to the production of inflammatory molecules and damaging neurons, in turn resulting in neurocognitive impairment (Kaul et al 2001 ; Ramesh et al 2013 ).…”