Abstract
Alzheimer’s disease (AD) still remains an enigma for researchers and clinicians. The onset of AD is insidious, gradually progressive and multifactorial. The recent accumulated scientific evidences suggests that the pathological changes resemble the autoimmune-driven self-sustaining inflammatory process as a result of prolonged oxidative stress and immune dyshomeostasis. Apart from aging, during life span various other factors—mainly environmental, lifestyle, chronic stress, polymicrobial infections and neuroendocrine functions—affect the immune system. Here, we provide crosstalk among “trigger insults/inflammatory stimulus” i.e., polymicrobial infection, chronic stress, pro-inflammatory diet and cholinergic signaling to put forward a “Systemic Immune Dyshomeostasis” model as to connect the events leading to AD development and progression. Our model implicates altered cholinergic signaling and suggests pathological stages with various modifiable risk factors and triggers at different chronological age and stage of cognitive decline. The search of specific autoantibodies for AD which may serve as the suitable blood/CSF biomarkers should be actively pursued for the early diagnosis of AD. The preventive and therapeutic strategies should be directed towards maintaining the normal functioning of the immune system throughout the life span and specific modulation of the immune responses in the brain depending on the stage of changes in brain.
Highlights
Alzheimer’s disease (AD), the most common dementia subtype, affected 50 million individuals globally in 2018
We have presented the crosstalk among ‘‘trigger insults/inflammatory stimulus,’’ i.e., polymicrobial infection, chronic stress, pro-inflammatory diet and cholinergic signaling and proposed a model that potentially connects the events leading to AD development and progression
The review highlights some of the recent findings on how different inflammatory responses exacerbate neurodegenerative processes associated with AD and how the systemic immune changes, along with a litany of other processes, including chronic stress, cholinergic signaling defects, polymicrobial invasion and other chronic insults, may be responsible for many of these changes
Summary
Alzheimer’s disease (AD), the most common dementia subtype, affected 50 million individuals globally in 2018. The periodic use of supplements—mainly omega-3 fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], vitamin B12, vitamin E, folic acid, curcumin with black pepper (piperine), grape seed extracts (gallic acid and catechins), Withania Somnifera (withanolide withaferin A), Ginko Biloba (ginkgolide), barberry (berberine), ginseng (Gintonin), Resveratrol and probiotics—can prevent autoimmune activity and inflammation through different mechanisms and can be beneficial in preventing early onset of cognitive impairment among at-risk individuals (Daulatzai, 2015; Viña and Sanz-Ros, 2018; Wang et al, 2018) These lifestyle modifications may deal with trigger insults and maintain the immune homeostasis, preventing or delaying BBB dysfunction and allowing crossreactive antibodies to enter into the CNS through cerebral vasculature. Other important supplement candidates are Ginkgo Biloba (Increase NGF), Withania Somnifera (steroidlike activity), Glycyrrhiza glabra or Tripterygium wilfordii [heat shock protein 90 (Hsp90) inhibitors], Centella asiatica (increases neurite outgrowth in the presence of NGF), vitamin D with zinc and drug selegiline (elevates NGF, BDNF, and GDNF) (Aloe et al, 1994; Sehgal et al, 2012; Berti et al, 2015; Dal Piaz et al, 2015; Gray et al, 2017; Puttarak et al, 2017; Campanella et al, 2018; Farooqui et al, 2018; Kandiah et al, 2019; Park et al, 2019; Talwar et al, 2019)
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