Alzheimer's disease (AD) is characterized by progressive memory loss and cognitive function deficits. There are two major pathological hallmarks that contribute to the pathogenesis of AD which are the presence of extracellular amyloid plaques composed of amyloid-β (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau. Despite extensive research that has been done on Aβ in the last two decades, therapies targeting Aβ were not very fruitful at treating AD as the efficacy of Aβ therapies observed in animal models is not reflected in human clinical trials. Hence, tau-directed therapies have received tremendous attention as the potential treatments for AD. Tauopathies are closely correlated with dementia and immunotherapy has been effective at reducing tau pathology and improving cognitive deficits in animal models. Thus, in this review article, we discussed the pathological mechanism of tau proteins, the key factors contributing to tauopathies, and therapeutic approaches for tauopathies in AD based on the recent progress in tau-based research.
Alzheimer's disease (AD) is a neurodegenerative disease that is imposing an increasing burden on society. Currently, AD is the leading cause of senile dementia worldwide. Despite the long existence of AD, there is lack of therapies for AD, suggesting that new and effective treatment strategy must be explored. At present, sirtuin pathway has attracted attention from the researchers due to its promising results in laboratory models of aging. In addition, our understanding in the roles of sirtuin 6 in AD has expanded. It has been identified to be involved in telomere maintenance, DNA repair, genome integrity, energy metabolism, and inflammation, which ultimately regulate life span. Recent findings also demonstrate that sirtuin 6 is lacking in AD patients, proposing that it can be a new potential therapeutic target in AD. Therefore, exploring on how sirtuin 6 is related in AD manifestation may accelerate the research of AD further and benefits future AD patients. Keeping that in mind, this review aims to highlight the possible roles of sirtuin 6 in AD manifestation.
The extracellular ligand, Wnt, and its receptors are involved in sign al transduction and play an important role in axis formation and neural development. In neurodegenerative disorders such as Alzheimer's disease (AD), a decrease of the intracellular Wnt effector, β-catenin, has been linked to amyloid-β-peptide-induced neurotoxicity. Despite this knowledge, targeting Wnt inhibitors as potential biomarkers has not been explored, and harnessing Wnt activators as therapeutic candidates remains largely not investigated. A wide acting family of Wnt mediators, secreted frizzled-related proteins (sFRPs), has not been probed so far as molecular indicators of disease occurrence and progression of Alzheimer's. Unlike the effect of the Dickkopf (DKK) family of Wnt antagonists on AD, the sFRP molecules have a more pleiotropic impact on the Wnt signaling cascade and probably have a far-reaching involvement in neurodegeneration. The role of sFRPs has been poorly described in AD, and in this review, we analyze the present status of the role of sFRPs on neurodegeneration, their likely involvement, and potential implications in treatment modalities of AD. This information would provide valuable clues for the development of potential therapeutic targets for aberrant neurodegenerative disorders.
Neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by progressive neuronal loss and pathological accumulation of some proteins. Developing new biomarkers for both diseases is highly important for the early diagnosis and possible development of neuro-protective strategies. Serum antibodies (AIAs) against neuronal proteins are potential biomarkers for AD and PD that may be formed in response to their release into systemic circulation after brain damage. In the present study, two AIAs (tubulin and tau) were measured in sera of patients of PD and AD, compared to healthy controls. Results showed that both antibodies were elevated in patients with PD and AD compared to match controls. Curiously, the profile of elevation of antibodies was different in both diseases. In PD cases, tubulin and tau AIAs levels were similar. On the other hand, AD patients showed more elevation of tau AIAs compared to tubulin. Our current results suggested that AIAs panel could be able to identify cases with neuro-degeneration when compared with healthy subjects. More interestingly, it is possible to differentiate between PD and AD cases through identifying specific AIAs profile for each neurodegenerative states.
Emerging findings point toward an important interconnection between epilepsy and Alzheimer's disease (AD) pathogenesis. Patients with epilepsy (PWE) commonly exhibit cognitive impairment similar to AD patients, who in turn are at a higher risk of developing epilepsy compared to age-matched controls. To date, no disease-modifying treatment strategy is available for either epilepsy or AD, reflecting an immediate need for exploring common molecular targets, which can delineate a possible mechanistic link between epilepsy and AD. This review attempts to disentangle the interconnectivity between epilepsy and AD pathogenesis via the crucial contribution of Tau protein. Tau protein is a microtubule-associated protein (MAP) that has been implicated in the pathophysiology of both epilepsy and AD. Hyperphosphorylation of Tau contributes to the different forms of human epilepsy and inhibition of the same exerted seizure inhibitions and altered disease progression in a range of animal models. Moreover, Tau-protein-mediated therapy has demonstrated promising outcomes in experimental models of AD. In this review, we discuss how Tau-related mechanisms might present a link between the cause of seizures in epilepsy and cognitive disruption in AD. Untangling this interconnection might be instrumental in designing novel therapies that can minimize epileptic seizures and cognitive deficits in patients with epilepsy and AD.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.
Alzheimer's disease (AD) is a primary cause of dementia in the middle-aged and elderly worldwide. Animal models for AD are widely used to study the disease mechanisms as well as to test potential therapeutic agents for disease modification. Among the non-genetically manipulated neuroinflammation models for AD, lipopolysaccharide (LPS)-induced animal model is commonly used. This review paper aims to discuss the possible factors that influence rats' response following LPS injection. Factors such as dose of LPS, route of administration, nature and duration of exposure as well as age and gender of animal used should be taken into account when designing a study using LPS-induced memory impairment as model for AD.
Neuroblastoma cell lines such as SH-SY5Y are the most frequently utilized models in neurodegenerative research, and their use has advanced the understanding of the pathology of neurodegeneration over the past few decades. In Alzheimer's disease (AD), several pathogenic mutations have been described, all of which cause elevated levels of pathological hallmarks such as amyloid-beta (Aβ). Although the genetics of Alzheimer's disease is well known, familial AD only accounts for a small number of cases in the population, with the rest being sporadic AD, which contains no known mutations. Currently, most of the in vitro models used to study AD pathogenesis only examine the level of Aβ42 as a confirmation of successful model generation and only perform comparisons between wild-type APP and single mutants of the APP gene. Recent findings have shown that the Aβ42/40 ratio in cerebrospinal fluid (CSF) is a better diagnostic indicator for AD patients than is Aβ42 alone and that more extensive Aβ formation, such as accumulation of intraneuronal Aβ, Aβ plaques, soluble oligomeric Aβ (oAβ), and insoluble fibrillar Aβ (fAβ) occurs in TgCRND8 mice expressing a double-mutant form (Swedish and Indiana) of APP, later leading to greater progressive impairment of the brain. In this study, we generated SH-SY5Y cells stably transfected separately with wild-type APP, the Swedish mutation of APP, and the Swedish and Indiana mutations of APP and evaluated the APP expression as well as the Aβ42/40 ratio in those cells. The double-mutant form of APP (Swedish/Indiana) expressed markedly high levels of APP protein and showed a high Aβ2/40 ratio compared to wild-type and single-mutant cells.
Alzheimer's disease (AD), which largely affects the elderly, has become a global burden. Patients with AD have both short- and long-term memory impairments. The neuronal loss in AD occurs due to abnormally folded amyloid beta proteins and aggregation of hyperphosphorylated tau proteins in the brain. Eventually, amyloid plaques and neurofibrillary tangles are formed, which subsequently disintegrate the neuronal transport system. There are several factors which are involved in AD pathogenesis, including oxidative stress, inflammation and the presence of metal ions. The modern therapies utilized for AD treatment have many adverse effects, driving the quest for more safe and effective medications. Many dietary components, including different types of fruits, vegetables, spices, and marine products as well as a Mediterranean diet, are a good source of antioxidants and have anti-inflammatory properties, with many showing substantial potential against AD pathogenesis. In this review, we discuss the potential of these foods for treating AD and opportunities for developing disease-targeted drugs from active compounds extracted from natural dietary products.
Alzheimer's disease (AD) is an increasingly prevalent neurological disorder of the central nervous system. There is growing evidence that amyloidogenesis is a pathological hallmark for AD; this leads to the formation of senile plaques. Naringenin is a bioflavonoid which has neuroprotective effects through its antioxidant and anti-inflammatory properties. However, its clinical usage is limited due to its inefficient transport across biological membranes. In the present study, a naringenin nanoemulsion was prepared and its neuroprotective effects were tested against β-amyloid induced neurotoxicity in a human neuroblastoma cell line (SH-SY5Y). The optimised, naringenin-loaded nanoemulsion formulation had a droplet size of 113.83 ± 3.35 nm and around 50 nm, as assessed respectively by photon correlation spectroscopy and transmission electron microscopy. The preparation showed a low polydispersity index (0.312 ± 0.003), a high zeta potential (12.4 ± 1.05) and a high percentage transmittance (97.01%). The neuroprotective activity of naringenin nanoemulsions was determined by assessing their ability to protect SH-SY5Y neuroblastoma cells against the neurotoxic effect of beta amyloid (Aβ). Aβ-induced production of reactive oxygen species (ROS), amyloid precursor protein (APP), β-secretase (BACE), total tau and phosphorylated tau (pT231) was also determined. The naringenin loaded nanoemulsion significantly alleviated the direct neurotoxic effects of Aβ on SH-SY5Y cells; this was associated with a down-regulation of APP and BACE expression, indicating reduced amyloidogenesis. Furthermore, it decreased the levels of phosphorylated tau in SH-SY5Y cells exposed to Aβ. These results suggest that a naringenin-loaded nanoemulsion could be a promising agent for the treatment of Alzheimer's disease.
The innate immune system and inflammatory response in the brain have critical impacts on the pathogenesis of many neurodegenerative diseases including Alzheimer's disease (AD). In the central nervous system (CNS), the innate immune response is primarily mediated by microglia. However, non-glial cells such as neurons could also partake in inflammatory response independently through inflammasome signalling. The NLR family pyrin domain-containing 1 (NLRP1) inflammasome in the CNS is primarily expressed by pyramidal neurons and oligodendrocytes. NLRP1 is activated in response to amyloid-β (Aβ) aggregates, and its activation subsequently cleaves caspase-1 into its active subunits. The activated caspase-1 proteolytically processes interleukin-1β (IL-1β) and interleukin-18 (IL-18) into maturation whilst co-ordinately triggers caspase-6 which is responsible for apoptosis and axonal degeneration. In addition, caspase-1 activation induces pyroptosis, an inflammatory form of programmed cell death. Studies in murine AD models indicate that the Nlrp1 inflammasome is indeed upregulated in AD and neuronal death is observed leading to cognitive decline. However, the mechanism of NLRP1 inflammasome activation in AD is particularly elusive, given its structural and functional complexities. In this review, we examine the implications of the human NLRP1 inflammasome and its signalling pathways in driving neuroinflammation in AD.
Oxidative stress plays a crucial role in Alzheimer's disease (AD) from its prodromal stage of mild cognitive impairment. There is an interplay between oxidative stress and the amyloid β (Aβ) cascade via various mechanisms including mitochondrial dysfunction, lipid peroxidation, protein oxidation, glycoxidation, deoxyribonucleotide acid damage, altered antioxidant defense, impaired amyloid clearance, inflammation and chronic cerebral hypoperfusion. Based on findings that indicate that oxidative stress plays a major role in AD, oxidative stress has been considered as a therapeutic target of AD. In spite of favorable preclinical study outcomes, previous antioxidative components, including a single antioxidative supplement such as vitamin C, vitamin E or their mixtures, did not clearly show any therapeutic effect on cognitive decline in AD. However, novel antioxidative supplements can be beneficial for AD patients. In this review, we summarize the interplay between oxidative stress and the Aβ cascade, and introduce novel antioxidative supplements expected to prevent cognitive decline in AD.
The endosomal-lysosomal system mediates the process of protein degradation through endocytic pathway. This system consists of early endosomes, late endosomes, recycling endosomes and lysosomes. Each component in the endosomal-lysosomal system plays individual crucial role and they work concordantly to ensure protein degradation can be carried out functionally. Dysregulation in the endosomal-lysosomal system can contribute to the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). In AD endosomal-lysosomal abnormalities are the earliest pathological features to note and hence it is important to understand the involvement of endosomal-lysosomal dysfunction in the pathogenesis of AD. In-depth understanding of this dysfunction can allow development of new therapeutic intervention to prevent and treat AD.
The pathophysiological link between type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD) has been suggested in several reports. Few findings suggest that T2DM has strong link in the development process of AD, and the complete mechanism is yet to be revealed. Formation of amyloid plaques (APs) and neurofibrillary tangles (NFTs) are two central hallmarks in the AD. APs are the dense composites of β-amyloid protein (Aβ) which accumulates around the nerve cells. Moreover, NFTs are the twisted fibers containing hyperphosphorylated tau proteins present in certain residues of Aβ that build up inside the brain cells. Certain factors contribute to the aetiogenesis of AD by regulating insulin signaling pathway in the brain and accelerating the formation of neurotoxic Aβ and NFTs via various mechanisms, including GSK3β, JNK, CamKII, CDK5, CK1, MARK4, PLK2, Syk, DYRK1A, PPP, and P70S6K. Progression to AD could be influenced by insulin signaling pathway that is affected due to T2DM. Interestingly, NFTs and APs lead to the impairment of several crucial cascades, such as synaptogenesis, neurotrophy, and apoptosis, which are regulated by insulin, cholesterol, and glucose metabolism. The investigation of the molecular cascades through insulin functions in brain contributes to probe and perceive progressions of diabetes to AD. This review elaborates the molecular insights that would help to further understand the potential mechanisms linking T2DM and AD.
Alzheimer's disease (AD) is the most common CNS disorder occurring worldwide. There is neither proven effective prevention for AD nor a cure for patients with this disorder. Hence, there is an urgent need to develop safer and more efficacious drugs to help combat the tremendous increase in disease progression. The present review is an attempt at discussing the treatment strategies and drugs under clinical trials governing the modulation of neurotransmitter. Therefore, looking at neurotransmitter abnormalities, there is an urge for developing the pharmacological approaches aimed at correcting those abnormalities and dysfunctioning. In addition, this review also discusses the drugs that are in Phase III trials for the treatment of AD. Despite advances in treatment strategies aimed at correcting neurotransmitter abnormalities, there exists a need for the development of drug therapies focusing on the attempts to remove the pathogenomic protein deposits, thus combating the disease progression.
Extracellular senile plaques and intracellular neurofibrillary tangles are the neuropathological findings of the Alzheimer's disease (AD). Based on the amyloid cascade hypothesis, the main component of senile plaques, the amyloid-beta (Aβ) peptide, and its derivative called amyloid precursor protein (APP) both have been found to place their central roles in AD development for years. However, the recent therapeutics have yet to reverse or halt this disease. Previous evidence demonstrates that the accumulation of Aβ peptides and APP can exert neurotoxicity and ultimately neuronal cell death. Hence, we discuss the mechanisms of excessive production of Aβ peptides and APP serving as pathophysiologic stimuli for the initiation of various cell signalling pathways including apoptosis, necrosis, necroptosis and autophagy which lead to neuronal cell death. Conversely, the activation of such pathways could also result in the abnormal generation of APP and Aβ peptides. An elucidation of actions of APP and its metabolite, Aβ, could be vital in suggesting novel therapeutic opportunities.
Recent evidence suggests that the formation of soluble amyloid β (Aβ) aggregates with high toxicity, such as oligomers and protofibrils, is a key event that causes Alzheimer's disease (AD). However, understanding the pathophysiological role of such soluble Aβ aggregates in the brain in vivo could be difficult due to the lack of a clinically available method to detect, visualize, and quantify soluble Aβ aggregates in the brain. We had synthesized a novel fluorinated curcumin derivative with a fixed keto form, named as Shiga-Y51, which exhibited high selectivity to Aβ oligomers in vitro. In this study, we investigated the in vivo detection of Aβ oligomers by fluorine-19 (19F) magnetic resonance imaging (MRI) using Shiga-Y51 in an APP/PS1 double transgenic mouse model of AD. Significantly high levels of 19F signals were detected in the upper forebrain region of APP/PS1 mice compared with wild-type mice. Moreover, the highest levels of Aβ oligomers were detected in the upper forebrain region of APP/PS1 mice in enzyme-linked immunosorbent assay. These findings suggested that 19F-MRI using Shiga-Y51 detected Aβ oligomers in the in vivo brain. Therefore, 19F-MRI using Shiga-Y51 with a 7 T MR scanner could be a powerful tool for imaging Aβ oligomers in the brain.
Aggregation of tau into neurofibrillary tangles (NFTs) is characteristic of tauopathies, including Alzheimer's disease. Recent advances in tau imaging have attracted much attention because of its potential contributions to early diagnosis and monitoring of disease progress. Fluorine-19 magnetic resonance imaging (19 F-MRI) may be extremely useful for tau imaging once a high-quality probe has been formulated. In this investigation, a novel fluorine-19-labeling compound has been developed as a probe for tau imaging using 19 F-MRI. This compound is a buta-1,3-diene derivative with a polyethylene glycol side chain bearing a CF3 group and is known as Shiga-X35. Female rTg4510 mice (a mouse model of tauopathy) and wild-type mice were intravenously injected with Shiga-X35, and magnetic resonance imaging of each mouse's head was conducted in a 7.0-T horizontal-bore magnetic resonance scanner. The 19 F-MRI in rTg4510 mice showed an intense signal in the forebrain region. Analysis of the signal intensity in the forebrain region revealed a significant accumulation of fluorine-19 magnetic resonance signal in the rTg4510 mice compared with the wild-type mice. Histological analysis showed fluorescent signals of Shiga-X35 binding to the NFTs in the brain sections of rTg4510 mice. Data collected as part of this investigation indicate that 19 F-MRI using Shiga-X35 could be a promising tool to evaluate tau pathology in the brain.
The interlink between diabetes mellitus and neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD) has been identified by several researchers. Patients with Type-2 Diabetes Mellitus (T2DM) are found to be affected with cognitive impairments leading to learning and memory deficit, while patients with Type-1 Diabetes Mellitus (T1DM) showed less severe levels of these impairments in the brain. This review aimed to discuss the connection between insulin with the pathophysiology of neurodegenerative diseases (AD and PD) and the current therapeutic approached mediated through insulin for management of neurodegenerative diseases. An extensive literature search was conducted using keywords "insulin"; "insulin resistance"; "Alzheimer's disease"; "Parkinson's disease" in public domains of Google scholar, PubMed, and ScienceDirect. Selected articles were used to construct this review. Studies have shown that impaired insulin signaling contributes to the accumulation of amyloid-β, neurofibrillary tangles, tau proteins and α-synuclein in the brain. Whereas, improvement in insulin signaling slows down the progression of cognitive decline. Various therapeutic approaches for altering the insulin function in the brain have been researched. Besides intranasal insulin, other therapeutics like PPAR-γ agonists, neurotrophins, stem cell therapy and insulin-like growth factor-1 are under investigation. Research has shown that insulin insensitivity in T2DM leads to neurodegeneration through mechanisms involving a variety of extracellular, membrane receptor, and intracellular signaling pathway disruptions. Some therapeutics, such as intranasal administration of insulin and neuroactive substances have shown promise but face problems related to genetic background, accessibility to the brain, and invasiveness of the procedures.
Alzheimer's disease is an irreversible neurodegenerative disease, which accounts for most dementia cases. Neuroinflammation is increasingly recognised for its roles in Alzheimer's disease pathogenesis which, in part, links amyloid-beta to neuronal death. Neuroinflammatory signalling can be exhibited by neurons themselves, potentially leading to widespread neuronal cell death, although neuroinflammation is commonly associated with glial cells. The presence of the inflammasomes such as nucleotide-binding leucine-rich repeat receptors protein 1 in neurons accelerates amyloid-beta -induced neuroinflammation and has been shown to trigger neuronal pyroptosis in murine Alzheimer's disease models. However, the pathways involved in amyloid-beta activation of inflammasomes have yet to be elucidated. In this study, a gene trap mutagenesis approach was utilised to resolve the genes functionally involved in inflammasome signalling within neurons, and the mechanism behind amyloid-beta-induced neuronal death. The results indicate that amyloid-beta significantly accelerated neuroinflammatory cell death in the presence of a primed inflammasome (the NLR family pyrin domain-containing 1). The mutagenesis screen discovered the atypical mitochondrial Ras homolog family member T1 as a significant contributor to amyloid-beta-induced inflammasome -mediated neuronal death. The mutagenesis screen also identified two genes involved in transforming growth factor beta signalling, namely Transforming Growth Factor Beta Receptor 1 and SNW domain containing 1. Additionally, a gene associated with cytoskeletal reorganisation, SLIT-ROBO Rho GTPase Activating Protein 3 was found to be neuroprotective. In conclusion, these genes could play important roles in inflammasome signalling in neurons, which makes them promising therapeutic targets for future drug development against neuroinflammation in Alzheimer's disease.