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Alzheimer's disease (AD) is a progressive neurological disorder characterized by memory loss, cognitive decline, and behavioral changes. Immunotherapy aims to harness the immune system to target the underlying pathology of AD and has shown promise as a disease-modifying treatment for AD. By focusing on the underlying disease pathogenesis and encouraging the removal of abnormal protein aggregates in the brain, immunotherapy shows promise as a potential treatment for AD. The development of immunotherapy for AD began with early attempts to use antibodies to target beta-amyloid. The amyloid hypothesis which suggests that the accumulation of beta-amyloid in the brain triggers the pathological cascade that leads to AD has been a driving force behind the development of immunotherapy for AD. However, recent clinical trials of monoclonal antibodies targeting amyloid-β have shown mixed results, highlighting the need for further research into alternative immunotherapy approaches. Additionally, the safety and efficacy of immunotherapy for AD remain an area of active investigation. Some immunotherapeutic approaches have shown promise, while others have been associated with significant side effects, including inflammation of the brain. Sleep has a significant impact on various physiological processes, including the immune system, and has been linked to the pathogenesis of AD. Thus, improving sleep quality and duration may benefit the immune system and potentially enhance the effectiveness of immunotherapeutic approaches for AD. In this review, we discussed the promises of immunotherapy as a disease-modifying treatment for AD as well as possible methods to improve the efficacy and safety of immunotherapy to achieve better therapeutic outcomes.

Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Alzheimer's disease (AD) is characterized by the progressive degeneration of neuronal cells. With the increase in aged population, there is a prevalence of irreversible neurodegenerative changes, causing a significant mental, social, and economic burden globally. The factors contributing to AD are multidimensional, highly complex, and not completely understood. However, it is widely known that aging, neuroinflammation, and excessive production of reactive oxygen species (ROS), along with other free radicals, substantially contribute to oxidative stress and cell death, which are inextricably linked. While oxidative stress is undeniably important in AD, limiting free radicals and ROS levels is an intriguing and potential strategy for deferring the process of neurodegeneration and alleviating associated symptoms. Therapeutic compounds from natural sources have recently become increasingly accepted and have been effectively studied for AD treatment. These phytocompounds are widely available and a multitude of holistic therapeutic efficiencies for treating AD owing to their antioxidant, anti-inflammatory, and biological activities. Some of these compounds also function by stimulating cholinergic neurotransmission, facilitating the suppression of beta-site amyloid precursor protein-cleaving enzyme 1, α-synuclein, and monoamine oxidase proteins, and deterring the occurrence of AD. Additionally, various phenolic, flavonoid, and terpenoid phytocompounds have been extensively described as potential palliative agents for AD progression. Preclinical studies have shown their involvement in modulating the cellular redox balance and minimizing ROS formation, displaying them as antioxidant agents with neuroprotective abilities. This review emphasizes the mechanistic role of natural products in the treatment of AD and discusses the various pathological hypotheses proposed for AD.

For the maintenance of cellular homeostasis and energy metabolism, an uninterrupted supply of oxygen (O2) is routinely required in the brain. However, under the impaired level of O2 (hypoxia) or reduced blood flow (ischemia), the tissues are not sufficiently oxygenated, which triggers disruption of cellular homeostasis in the brain. Hypoxia is known to have a notable effect on controlling the expression of proteins involved in a broad range of biological processes varying from energy metabolism, erythropoiesis, angiogenesis, neurogenesis to mitochondrial trafficking and autophagy, thus facilitating neuronal cells to endure in deprived O2. On the contrary, hypoxia to the brain is a major source of morbidity and mortality in humans culminating in cognitive impairment, gradual muscle weakness, loss of motor activity, speech deficit, and paralysis as well as other pathological consequences. Further, hypoxia resulting in reduced O2 deliveries to brain tissues is supposed to cause neurodegeneration in both in vivo and in vitro models. Similarly, chronic exposure to hypoxia has also been reportedly involved in defective vessel formation. Such vascular abnormalities lead to altered blood flow, reduced nutrient delivery, and entry of otherwise restricted infiltrates, thereby limiting O2 availability to the brain and causing neurological disabilities. Moreover, the precise mechanistic role played by hypoxia in mediating key processes of the brain and alternatively, in triggering pathological signals associated with neurodegeneration remains mysterious. Therefore, this review elucidates the intricate role played by hypoxia in modulating crucial processes of the brain and their severity in neuronal damage. Additionally, the involvement of numerous pharmacological approaches to compensate hypoxia-induced neuronal damage has also been addressed, which may be considered as a potential therapeutic approach in hypoxia-mediated neurodegeneration.

The communication between neurons at synaptic junctions is an intriguing process that monitors the transmission of various electro-chemical signals in the central nervous system. Albeit any aberration in the mechanisms associated with transmission of these signals leads to loss of synaptic contacts in both the neocortex and hippocampus thereby causing insidious cognitive decline and memory dysfunction. Compelling evidence suggests that soluble amyloid-β (Aβ) and hyperphosphorylated tau serve as toxins in the dysfunction of synaptic plasticity and aberrant neurotransmitter (NT) release at synapses consequently causing a cognitive decline in Alzheimer's disease (AD). Further, an imbalance between excitatory and inhibitory neurotransmission systems induced by impaired redox signaling and altered mitochondrial integrity is also amenable for such abnormalities. Defective NT release at the synaptic junction causes several detrimental effects associated with altered activity of synaptic proteins, transcription factors, Ca2+ homeostasis, and other molecules critical for neuronal plasticity. These detrimental effects further disrupt the normal homeostasis of neuronal cells and thereby causing synaptic loss. Moreover, the precise mechanistic role played by impaired NTs and neuromodulators (NMs) and altered redox signaling in synaptic dysfunction remains mysterious, and their possible interlink still needs to be investigated. Therefore, this review elucidates the intricate role played by both defective NTs/NMs and altered redox signaling in synaptopathy. Further, the involvement of numerous pharmacological approaches to compensate neurotransmission imbalance has also been discussed, which may be considered as a potential therapeutic approach in synaptopathy associated with AD.

Alzheimer's disease (AD) is characterized by dementia, cognitive disabilities, and tauopathy. Tau is a microtubule associated protein that helps maintain the neuronal network. While phosphorylation of tau protein causes disruption of the microtubular network, dephosphorylation allows reconstitution of the microtubule network. Several kinases, e.g., MARK, MAPK, and protein kinase C, are known to hyperphosphorylate tau, leading to disruption of the microtubular network and formation of neurofibrillary tangles (NFTs), which are further glycosylated, glycated, and have lipid peroxide adducts that impair the neuronal transport system and affect memory formation and retention. Moreover, intracerebral administration of amyloid-β oligomers causes hyperphosphorylation of tau, but whether it is involved in the formation of NFTs is still unclear. Further, amyloid burden activates AMP-activated protein kinase that increases phosphorylation of tau at position Ser262/Ser356 and Ser396. Several phosphatases are present at low levels in AD brains indicating that their down regulation results in abnormal hyperphosphorylation of tau. However, evidence strengthens a possible link between tau phosphorylation and molecular chaperone mediated tau metabolism for the clearance of toxic tau accumulation and has a crucial role in tauopathy. Furthermore, accumulation of phosphorylated tau protein and the possibility of removing the toxic phosphorylated tau protein from the milieu indicates that the chaperone interacts with phosphorylated tau and promotes its degradation. For instance, Hsp90 and cdc37 regulate tau stability and phosphorylation dynamics whereas Hsp27 is able to modulate neuronal plasticity, while 14-3-3 is involved in the interaction of tau with small HSPs. Hsp70 ATPase acts as a modulator in AD therapeutics while Hsc70 rapidly engages tau after microtubular destabilization. Herein, we highlight the various causes of tauopathy and HSP-E3 ligase mediated therapeutics in AD.

Alzheimer's disease (AD) is a neurodegenerative process primarily characterized by amyloid-β (Aβ) agglomeration, neuroinflammation, and cognitive dysfunction. The prominent cause for dementia is the deposition of Aβ plaques and tau-neurofibrillary tangles that hamper the neuronal organization and function. Aβ pathology further affects numerous signaling cascades that disturb the neuronal homeostasis. For instance, Aβ deposition is responsible for altered expression of insulin encoding genes that lead to insulin resistance, and thereby affecting insulin signaling pathway and glucose metabolism in the brain. As a result, the common pathology of insulin resistance between Type-2 diabetes mellitus and AD has led AD to be proposed as a form of diabetes and termed 'Type-3 diabetes'. Since accumulation of Aβ is the prominent cause of neuronal toxicity in AD, its clearance is the prime requisite for therapeutic prospects. This purpose is expertly fulfilled by the potential role of Aβ degrading enzymes such as insulin degrading enzyme (IDE) and Neprilysin (NEP). Therefore, their molecular study is important to uncover the proteolytic and regulatory mechanism of Aβ degradation. Herein, (i) In silico sequential and structural analysis of IDE and NEP has been performed to identify the molecular entities for proteolytic degradation of Aβ in the AD brain, (ii) to analyze their catalytic site to demonstrate the enzymatic action played by IDE and NEP, (iii) to identify their structural homologues that could behave as putative partners of IDE and NEP with similar catalytic action and (iv) to illustrate various IDE- and NEP-mediated therapeutic approaches and factors for clearing Aβ in AD.