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.
Citation: Kiran Kumar Siddappaji, Shubha Gopal. Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches[J]. AIMS Neuroscience, 2021, 8(3): 357-389. doi: 10.3934/Neuroscience.2021020
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.
Alzheimer's disease
Amyloid-beta
Neurofibrillary Tangles
Amyloid Precursor Protein
soluble Amyloid Precursor Protein alpha
Amyloid Precursor Protein Intra Cellular Domain
N-Methyl-D-Aspartate Receptor
α-Amino-3-hydroxy-5-Methyl-4-isoxazole Propionic acid Receptor
nicotinic Acetylcholine Receptors
muscarinic Acetylcholine Receptors
soluble Amyloid Precursor Protein beta
Reactive Oxygen Species
Protein Kinase C
Protein Kinase A
Extracellular signal-Regulated Kinases2
Cyclin-Dependent Kinases 5
AcetylcholinEsterase
Cerebro Spinal Fluid
Positron Emission Tomography
Blood-Brain Barrier
Physical Exercise
Dementia with Lewy Bodies
FrontoTemporal Dementia
Magnetic Resonance Imaging
functional Magnetic Resonance Imaging
repetitive Transcranial Magnetic Stimulation
transcranial Electrical Stimulation
transcranial Direct Current Stimulation
transcranial Alternating Current Stimulation
transcranial Random Noise Stimulation
transcranial Pulsed Current Stimulation
Mild Cognitive Impairment
Dynamin-related protein-1
Presenilin-1
Presenilin-2
Insulin Degrading Enzyme
Parkinson's Disease
Apolipoprotein-E
Protein Kinase B
Glycogen synthase kinase 3α/β
Electron Transport Chain
Insulin-like Growth Factor-1
Interleukin-6
Nitrous Oxide Synthase-2
Nuclear Factor Kappa B
Lipoprotein Receptor-related Protein-1
Orexin-A
Orexin-B
G-Protein-Coupled Receptors
Orexin Receptor-type-1
Orexin Receptor-type-2
Brain-Derived Neurotrophic Factor
Obstructive Sleep Apnea (OSA)
Central Disorders of Hypersomnolence
Rapid Eye Movement
Electroencephalogram
Traumatic Brain Injury
123I-Meta-IodoBenzylGuanidine
[11C]-Pittsburgh compound B
Fluorine 18-labeled
Montreal Cognitive Assessment
Total tau
phosphorylated-tau
Visinin-Like Protein
Neuro Filament Light Protein
Heart Fatty Acid Binding Protein
Neuron-Specific Enolase
Chitinase-3-like protein-1
Tumor Necrosis Factor Ligand Superfamily member-10
Angiotensin-Converting Enzyme
triple-transgenic-AD
Voxel-Based Morphometry
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Figures(5) / Tables(1)
Kiran Kumar Siddappaji, Shubha Gopal. Molecular mechanisms in Alzheimer's disease and the impact of physical exercise with advancements in therapeutic approaches[J]. AIMS Neuroscience, 2021, 8(3): 357-389. doi: 10.3934/Neuroscience.2021020
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