Aging is a complex biological process that increases the risk of age-related cognitive degenerative diseases such as dementia, including Alzheimer's disease (AD), Lewy Body Dementia (LBD), and mild cognitive impairment (MCI). Even non-pathological aging of the brain can involve chronic oxidative and inflammatory stress, which disrupts the communication and balance between the brain and the immune system. There has been an increasingly strong connection found between chronic neuroinflammation and impaired memory, especially in AD. While microglia and astrocytes, the resident immune cells of the central nervous system (CNS), exerting beneficial effects during the acute inflammatory phase, during chronic neuroinflammation they can become more detrimental. Central cholinergic circuits are involved in maintaining normal cognitive function and regulating signaling within the entire cerebral cortex. While neuronal-glial cholinergic signaling is anti-inflammatory and anti-oxidative, central cholinergic neuronal degeneration is implicated in impaired learning, memory sleep regulation, and attention. Although there is evidence of cholinergic involvement in memory, fewer studies have linked the cholinergic anti-inflammatory and anti-oxidant pathways to memory processes during development, normal aging, and disease states. This review will summarize the current knowledge of cholinergic effects on microglia and astroglia, and their role in both anti-inflammatory and anti-oxidant mechanisms, concerning normal aging and chronic neuroinflammation.
Chronic neuroinflammation characterized by microglia reactivity is one of the main underlying processes in the initiation and progression of neurodegenerative diseases such as Alzheimer’s disease. This project characterized spatial memory during healthy aging and prolonged neuroinflammation in the chronic neuroinflammatory model, glial fibrillary acidic protein-interleukin 6 (GFAP-IL6). We investigated whether chronic treatment with the natural flavonoid, apigenin, could reduce microglia activation in the hippocampus and improve spatial memory. GFAP-IL6 transgenic and wild-type-like mice were fed with apigenin-enriched or control chow from 4 months of age and tested for spatial memory function at 6 and 22 months using the Barnes maze. Brain tissue was collected at 22 months to assess microgliosis and morphology using immunohistochemistry, stereology, and 3D single cell reconstruction. GFAP-IL6 mice showed age-dependent loss of spatial memory recall compared with wild-type-like mice. Chronic apigenin treatment decreased the number of Iba-1+ microglia in the hippocampus of GFAP-IL6 mice and changed microglial morphology. Apigenin did not reverse spatial memory recall impairment in GFAP-IL6 mice at 22 months of age. GFAP-IL6 mice may represent a suitable model for age-related neurodegenerative disease. Chronic apigenin supplementation significantly reduced microglia activation, but this did not correspond with spatial memory improvement in the Barnes Maze.
The Australian rainforest is a rich source of medicinal plants that have evolved in the face of dramatic environmental challenges over a million years due to its prolonged geographical isolation from other continents. The rainforest consists of an inherent richness of plant secondary metabolites that are the most intense in the rainforest. The search for more potent and more bioavailable compounds from other plant sources is ongoing, and our short review will outline the pathways from the discovery of bioactive plants to the structural identification of active compounds, testing for potency, and then neuroprotection in a triculture system, and finally, the validation in an appropriate neuro-inflammatory mouse model, using some examples from our current research. We will focus on neuroinflammation as a potential treatment target for neurodegenerative diseases including multiple sclerosis (MS), Parkinson’s (PD), and Alzheimer’s disease (AD) for these plant-derived, anti-inflammatory molecules and highlight cytokine suppressive anti-inflammatory drugs (CSAIDs) as a better alternative to conventional nonsteroidal anti-inflammatory drugs (NSAIDs) to treat neuroinflammatory disorders.
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