Alzheimer’s disease (AD) is an incurable, neuropsychiatric, pathological condition that deteriorates the worth of geriatric lives. AD is characterized by aggregated senile amyloid plaques, neurofibrillary tangles, neuronal loss, gliosis, oxidative stress, neurotransmitter dysfunction, and bioenergetic deficits. The changes in GIT composition and harmony have been recognized as a decisive and interesting player in neuronal pathologies including AD. Microbiota control and influence the oxidoreductase status, inflammation, immune system, and the endocrine system through which it may have an impact on the cognitive domain. The altered and malfunctioned state of microbiota is associated with minor infections to complicated illnesses that include psychosis and neurodegeneration, and several studies show that microbiota regulates neuronal plasticity and neuronal development. The altered state of microbiota (dysbiosis) may affect behavior, stress response, and cognitive functions. Chronic stress-mediated pathological progression also has a well-defined role that intermingles at various physiological levels and directly impacts the pathological advancement of AD. Chronic stress-modulated alterations affect the well-established pathological markers of AD but also affect the gut–brain axis through the mediation of various downstream signaling mechanisms that modulate the microbial commensals of GIT. The extensive literature reports that chronic stressors affect the composition, metabolic activities, and physiological role of microbiota in various capacities. The present manuscript aims to elucidate mechanistic pathways through which stress induces dysbiosis, which in turn escalates the neuropathological cascade of AD. The stress–dysbiosis axis appears a feasible zone of work in the direction of treatment of AD.

Stress threatens the homeostasis and mobilizes a plethora of adaptive physiological and behavioral changes via the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic nervous system. The HPA axis influences the pituitary gland, hypothalamus and adrenal gland via a complex set of positive and negative feedback system. The feedback system operates in a well regulated neuroendocrine manner to reestablish the threatened body equilibrium. The HPA axis secreted major product is a glucocorticoid (cortisol) which is kept within a physiologically optimal range and serves to accomplish the various physiological functions crucial for survival. In chronically stressed individuals dishabituation of HPA axis is followed by increased release of glucocorticoids and catecholamines. Higher secretion of glucocorticoids influences glucose metabolism by promoting gluconeogenesis in the liver, suppressing glucose uptake (adipocytes and skeletal muscles), promoting lipolysis in adipocytes, suppressing insulin secretion, inflicting insulin resistance and inflammation. These biological changes alter neuroendocrine mechanisms and lead to maladaptive congregation of events that form the underlying cause of development of Type 2 diabetes (T2D). The currently reviewed evidences advocate that targeting stress mediated hypersecretion of glucocorticoids may be a viable approach for the treatment of T2D and to reinstate glucose homeostasis.

Alzheimer’s disease (AD) is a chronic intensifying incurable progressive disease leading to neurological deterioration manifested as impairment of memory and executive brain functioning affecting the physical ability like intellectual brilliance, common sense in patients. The recent therapeutic approach in Alzheimer's disease is only the symptomatic relief further emerging the need for therapeutic strategies to be targeted in managing the underlying silent killing progression of dreaded pathology. Therefore, the current research direction is focused on identifying the molecular mechanisms leading to the evolution of the understanding of the neuropathology of Alzheimer's disease. The resultant saturation in the area of current targets (amyloid β, τ Protein, oxidative stress etc.) has led the scientific community to rethink of the mechanistic neurodegenerative pathways and reprogram the current research directions. Although, the role of stress has been recognized for many years and contributing to the development of cognitive impairment, the area of stress has got the much-needed impetus recently and is being recognized as a modifiable menace for AD. Stress is an unavoidable human experience that can be resolved and normalized but chronic activation of stress pathways unsettle the physiological status. Chronic stress mediated activation of neuroendocrine stimulation is generally linked to a high risk of developing AD. Chronic stress-driven physiological dysregulation and hypercortisolemia intermingle at the neuronal level and leads to functional (hypometabolism, excitotoxicity, inflammation) and anatomical remodeling of the brain architecture (senile plaques, τ tangles, hippocampal atrophy, retraction of spines) ending with severe cognitive deterioration. The present review is an effort to collect the most pertinent evidence that support chronic stress as a realistic and modifiable therapeutic earmark for AD and to advocate glucocorticoid receptors as therapeutic interventions.

Acetylcholinesterase (AChE) is one of the key enzyme targets that have been used clinically for the management of Alzheimer’s Disorder (AD). Numerous reports in the literature predict and demonstrate in-vitro, and in-silico anticholinergic activity of herbal molecules, however, majority of them failed to find clinical application. To address these issues, we developed a 2D-QSAR model that could efficiently predict the AChE inhibitory activity of herbal molecules along with predicting their potential to cross the blood-brain-barrier (BBB) to exert their beneficial effects during AD. Virtual screening of the herbal molecules was performed and amentoflavone, asiaticoside, astaxanthin, bahouside, biapigenin, glycyrrhizin, hyperforin, hypericin, and tocopherol were predicted as the most promising herbal molecules for inhibiting AChE. Results were validated through molecular docking, atomistic molecular dynamics simulations and Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) studies against human AChE (PDB ID: 4EY7). To determine whether or not these molecules can cross BBB to inhibit AChE within the central nervous system (CNS) for being beneficial for the management of AD, we determined a CNS Multi-parameter Optimization (MPO) score, which was found in the range of 1 to 3.76. Overall, the best results were observed for amentoflavone and our results demonstrated a PIC₅₀ value of 7.377 nM, molecular docking score of −11.5 kcal/mol, and CNS MPO score of 3.76. In conclusion, we successfully developed a reliable and efficient 2D-QSAR model and predicted amentoflavone to be the most promising molecule that could inhibit human AChE enzyme within the CNS and could prove beneficial for the management of AD. Communicated by Ramaswamy H. Sarma