Targeting Neuroinflammation as Disease Modifying Approach to Alzheimer’s Disease: Potential and Challenges

Abstract: Alzheimer's disease (AD) is the most common form of dementia, having characteristic clinical features of progressive memory loss and visuospatial, language, and cognitive impairment. In addition, patients often suffer from comorbid depression and aggression. Aging is a major contributing factor, though the exact pathophysiological involvement in the disease progression is debatable. Biologists demonstrate that AD is not a result of a single pathological incident. However, an uncontrolled myriad of events is responsible for the pathophysiological condition; hence, it is regarded as a multifaceted disease. Pathophysiologically, AD is described by having a long preclinical stage (proteinopathy accumulation stage), followed by a short prodromal/dementia stage (clinical symptom onset), as evident via biomarker studies. Specific and sensitive biomarkers are needed to track disease progression and treatment. Neuroinflammation is one of the cardinal pathophysiological events of AD that form a positive activation loop between proteinopathy and pro-inflammatory mediators. However, the starting point is inconclusive. The vital cells, like glia, known as brain scavenger cells, remain in harmony between their quiescent and activated morphological states during any stimulus and help to regulate the neuroinflammatory microenvironment. Hence, focusing on the dysfunctional microglia could be a novel therapeutic approach to managing neuroinflammation condition in AD. This review focuses on the translational evidence of anti-diabetic and anti-inflammatory candidates in AD management. It also highlights the importance of the microglia activation spectrum, eicosanoid signaling, cytokine signaling, and inflammatory mediators responsible for the neuroinflammation cascade. The repeated failure of single-approached therapies has diverted researchers’ attention to AD-modifying approaches and AD multimodal treatment plans. This review is an effort to brief the role of new players (like micronutrients and nutraceutical applications) that have been reported as helpful in suppressing AD severity. Apart from anti-diabetic candidates, various insulin-mimetic and insulin-sensitizer drugs have also been assessed to target insulin insensitivity to mitigate AD progression. However, these possibilities are in the investigational stage and not clinically established yet, though various AD animal models have verified the positive outcome.