Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches

Abstract

Alzheimer's disease (AD) is one of the most common, severe neurodegenerative brain disorder characterized by the accumulation of amyloid-beta plaques, neurofibrillary tangles in the brain causing neural disintegration, synaptic dysfunction, and neuronal death leading to dementia. Although many US-FDA-approved drugs like Donepezil, Rivastigmine, Galantamine are available in the market, their consumption reduces only the symptoms of the disease but fails in potency to cure the disease. This disease affects many individuals with aging. Combating the disease tends to be very expensive. This review focuses on biochemical mechanisms in the neuron both at normal and AD state with relevance to the tau hypothesis, amyloid hypothesis, the risk factors influencing dementia, oxidative stress, and neuroinflammation altogether integrated with neurodegeneration. A brief survey is carried out on available biomarkers in the diagnosis of the disease, drugs used for the treatment, and the challenges in approaching therapeutic targets in inhibiting the disease pathologies. This review conjointly assesses the demerits with the inefficiency of drugs to reach targets, their side effects, and toxicity. Optimistically, this review directs on the advantageous strategies in using nanotechnology-based drug delivery systems to cross the blood-brain barrier for improving the efficacy of drugs combined with a novel neuronal stem cell therapy approach. Determinately, this review aims at the natural, non-therapeutic healing impact of physical exercise on different model organisms and the effect of safe neuromodulation treatments using repetitive Transcranial Magnetic Stimulation (rTMS), transcranial Electrical Stimulation (tES) in humans to control the disease pathologies prominent in enhancing the synaptic function.

The effects of active rehabilitation on symptoms associated with tau pathology: An umbrella review. Implications for chronic traumatic encephalopathy symptom management

“…There are models which present exercise as a disease-modifying intervention for patients with tauopathies, offering a potential system which can also reverse and prevent further damage due to the presence of tauopathies. One mechanism proposes the ability exercise has to target factors which regulate pathogenic tau production and accumulation [ 42 , 43 ]. Another mechanism discusses how exercise is able to enhance cellular and molecular mechanisms that support a healthy neural environment, such as autophagic (impaired by pathogenic p-tau) and anti-inflammatory systems [ 43 ] which can counteract pro-inflammation-related neuronal damage triggered by pathogenic p-tau.…”

“…One mechanism proposes the ability exercise has to target factors which regulate pathogenic tau production and accumulation [ 42 , 43 ]. Another mechanism discusses how exercise is able to enhance cellular and molecular mechanisms that support a healthy neural environment, such as autophagic (impaired by pathogenic p-tau) and anti-inflammatory systems [ 43 ] which can counteract pro-inflammation-related neuronal damage triggered by pathogenic p-tau.…”

The Effects of Exercise on Aging-Induced Exaggerated Cytokine Responses: An Interdisciplinary Discussion

“…Alzheimer's disease (AD) is the most common neurodegenerative disorder, and its neuropathological hallmarks are β -amyloid (A β ) plaques and neurofibrillary tangles [ 34 ]. The inflammatory process has a fundamental role in the pathogenesis of AD and is related to AD neuroinflammation, including brain cells, such as microglia and astrocytes, the complement system, cytokines, and chemokines.…”

In Vivo Neuropharmacological Potential of Gomphandra tetrandra (Wall.) Sleumer and In-Silico Study against β-Amyloid Precursor Protein

“…It is an advanced neurodegenerative brain disorder that causes structural and functional damage to the brain. Clinically, AD is characterized by unconscious behavior, memory impairment, lack of emotion, dysfunctional changes in language and speech, fatigue, hallucinations, lack of self-sufficiency, a decline in muscle mass, and dependency on caretakers [1,2]. Physiologically, AD is caused due to mitochondrial dysfunction, formation of reactive species (oxygen and nitrogen), lipid peroxidation, nitrosative stress, protein aggregation, protein oxidation, amyloidopathy, tauopathies, CREB signaling pathway, GSK-3 hypothesis, DNA damage, depletion of endogenous antioxidant enzymes, proteasome dysfunction, microglial activation, neuroinflammation, neuroepigenetic modification, etc.…”