Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment

2018 ◽  
Vol 25 (26) ◽  
pp. 3141-3159 ◽  
Author(s):  
Leide Caroline dos Santos Picanco ◽  
Priscilla F. Ozela ◽  
Maiara de Fatima de Brito Brito ◽  
Abraao A. Pinheiro ◽  
Elias C. Padilha ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Functions ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
New Therapeutic Approaches ◽  
Cerebrospinal Fluid Biomarkers ◽  
Microscopic Features ◽  
And Behavior

Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.

scholarly journals Centella asiatica Protects d-Galactose/AlCl3 Mediated Alzheimer’s Disease-Like Rats via PP2A/GSK-3β Signaling Pathway in Their Hippocampus

2019 ◽  
Vol 20 (8) ◽  
pp. 1871 ◽  
Author(s):  
Samaila Musa Chiroma ◽  
Mohamad Taufik Hidayat Baharuldin ◽  
Che Norma Mat Taib ◽  
Zulkhairi Amom ◽  
Saravanan Jagadeesan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Functions ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Centella Asiatica ◽  
The Elderly ◽  
Aluminium Chloride ◽  
Gsk 3Β ◽  
First Time

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder more prevalent among the elderly population. AD is characterised clinically by a progressive decline in cognitive functions and pathologically by the presence of neurofibrillary tangles (NFTs), deposition of beta-amyloid (Aβ) plaque and synaptic dysfunction in the brain. Centella asiatica (CA) is a valuable herb being used widely in African, Ayurvedic, and Chinese traditional medicine to reverse cognitive impairment and to enhance cognitive functions. This study aimed to evaluate the effectiveness of CA in preventing d-galactose/aluminium chloride (d-gal/AlCl3) induced AD-like pathologies and the underlying mechanisms of action were further investigated for the first time. Results showed that co-administration of CA to d-gal/AlCl3 induced AD-like rat models significantly increased the levels of protein phosphatase 2 (PP2A) and decreased the levels of glycogen synthase kinase-3 beta (GSK-3β). It was further observed that, CA increased the expression of mRNA of Bcl-2, while there was minimal effect on the expression of caspase 3 mRNA. The results also showed that, CA prevented morphological aberrations in the connus ammonis 3 (CA 3) sub-region of the rat’s hippocampus. The results clearly demonstrated for the first time that CA could alleviate d-gal/AlCl3 induced AD-like pathologies in rats via inhibition of hyperphosphorylated tau (P-tau) bio-synthetic proteins, anti-apoptosis and maintenance of cytoarchitecture.

scholarly journals Cholinesterase Inhibitors Used for the Management of Alzheimer’s Disease: A Review

2021 ◽  
pp. 121-128
Author(s):  
Aayushi Singh ◽  
Asha Jha
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurofibrillary Tangles ◽  
Cognitive Functions ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Cholinergic Innervation ◽  
Basal Nucleus ◽  
Higher Cognitive Functions

Alzheimer’s disease (AD) is defined as a progressive neurodegenerative disorder that has lately become the top reason for dementia in the elderly population (usually above 60-65 years). As mentioned before, most AD cases are sporadic and have a late onset. This disease is characterized by impairment of higher cognitive functions like deficits in memory, language comprehension, coordination, etc. The primary pathophysiology behind Alzheimer’s disease is loss of cholinergic innervation due to the formation of neuritic (senile) amyloid-beta plaques and tau protein-containing neurofibrillary tangles (NFTs) in parts of the brain associated with memory functions. These neurofibrillary tangles (NFTs) and amyloid β plaques can cause the induction of other aetiologies of Alzhedisease-likes like neuroinflammation and central hyperexcitability. The brain's main regions affected by Alzheimer’s disease are the neocortex, the basal nucleus of Meynert, and the hippocampus. These areas are associated with higher cognitive functions like memory, arousal, attention, sensory processing, etc. Thus, cholinesterase inhibitors have been widely used as first-line drug therapy for symptomatic relief in Alzheimer’s disease. They function by inhibiting acetylcholinesterase or catabolizing it and henceforth enhancing synaptic availability of Acetylcholine. The commonly prescribed drugs of this class include donepezil, galantamine, physostigmine, metrifonate, and rivastigmine. This article will discuss the widely used cholinesterase inhibitors (old & new) for managing AD symptoms in detail.

scholarly journals Alzheimer’s Disease: Current and Future Treatments. A Review

2014 ◽  
Vol 2 (2) ◽  
pp. 56-63
Author(s):  
Evelyn Chou
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Nmda Antagonists ◽  
Disease Modifying Drugs ◽  
Plaque Deposition ◽  
The Future ◽  
Disease Modifying ◽  
Future Treatments

Alzheimer’s disease (AD) is a currently incurable neurodegenerative disorder whose treatment poses a big challenge. Proposed causes of AD include the cholinergic, amyloid and tau hypotheses. Current therapeutic treatments have been aimed at dealing with the neurotransmitter imbalance. These include cholinesterase inhibitors and N-Methyl-D-aspartate (NMDA) antagonists. However, current therapeutics have been unable to halt AD progression. Much research has gone into the development of disease-modifying drugs to interfere with the course of the disease. Approaches include secretase inhibition and immunotherapy aimed at reducing plaque deposition. However, these have not been successful in curing AD as yet. It is believed that the main reason why therapeutics have failed to work is that treatment begins too late in the course of the disease. The future of AD treatment thus appears to lie with prevention rather than cure. In this article, current therapeutics and, from there, the future of AD treatment are discussed.

A Systematic Review on Donepezil-based Derivatives as Potential Cholinesterase Inhibitors for Alzheimer’s Disease

2019 ◽  
Vol 26 (30) ◽  
pp. 5625-5648 ◽  
Author(s):  
Jan Korabecny ◽  
Katarina Spilovska ◽  
Eva Mezeiova ◽  
Ondrej Benek ◽  
Radomir Juza ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
Neurodegenerative Disorder ◽  
Memory Loss ◽  
Nmda Receptor Antagonist ◽  
Amyloid Burden ◽  
Ache Inhibitors ◽  
Intellectual Capacity ◽  
Β Amyloid

: Alzheimer’s Disease (AD) is a multifactorial progressive neurodegenerative disorder characterized by memory loss, disorientation, and gradual deterioration of intellectual capacity. Its etiology has not been elucidated yet. To date, only one therapeutic approach has been approved for the treatment of AD. The pharmacotherapy of AD has relied on noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist - memantine, and acetylcholinesterase (AChE) inhibitors (AChEIs) - tacrine, donepezil, rivastigmine and galantamine. Donepezil was able to ameliorate the symptoms related to AD mainly via AChE, but also through reduction of β-amyloid burden. This review presents the overview of donepezilrelated compounds as potential anti-AD drugs developed on the basis of cholinergic hypothesis to act as solely AChE and butyrylcholinesterase (BChE) inhibitors.

A Chronological Review of Potential Disease-Modifying Therapeutic Strategies for Alzheimer's Disease

2020 ◽  
Vol 26 (12) ◽  
pp. 1286-1299 ◽  
Author(s):  
Miren Ettcheto ◽  
Oriol Busquets ◽  
Triana Espinosa-Jiménez ◽  
Ester Verdaguer ◽  
Carme Auladell ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Function ◽  
Neurodegenerative Disorder ◽  
Late Onset ◽  
Wide Spectrum ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
New Therapeutic Approaches ◽  
Β Protein

: Late-onset Alzheimer’s disease (LOAD) is a neurodegenerative disorder that has become a worldwide health problem. This pathology has been classically characterized for its affectation on cognitive function and the presence of depositions of extracellular amyloid β-protein (Aβ) and intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated Tau protein. To this day, no effective treatment has been developed. : Multiple strategies have been proposed over the years with the aim of finding new therapeutic approaches, such as the sequestration of Aβ in plasma or the administration of anti-inflammatory drugs. Also, given the significant role of the insulin receptor in the brain in the proper maintenance of cognitive function, drugs focused on the amelioration of insulin resistance have been proposed as potentially useful and effective in the treatment of AD. In the present review, taking into account the molecular complexity of the disease, it has been proposed that the most appropriate therapeutic strategy is a combinatory treatment of several drugs that will regulate a wide spectrum of the described altered pathological pathways.

scholarly journals Hyperphosphorylation of tau by GSK-3β in Alzheimer’s disease: The interaction of Aβ and sphingolipid mediators as a therapeutic target

2013 ◽  
Vol 4 (4) ◽  
Author(s):  
Maja Jembrek ◽  
Mirjana Babić ◽  
Nela Pivac ◽  
Patrick Hof ◽  
Goran Šimić
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mammalian Cells ◽  
Neurodegenerative Disorder ◽  
Glycogen Synthase ◽  
Proteolytic Processing ◽  
Microtubule Assembly ◽  
Hyperphosphorylated Tau ◽  
Adequate Treatment ◽  
Gsk 3Β

AbstractAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the extracellular deposits of β amyloid peptides (Aβ) in senile plaques, and intracellular aggregates of hyperphosphorylated tau in neurofibrillary tangles (NFT). Although accumulation of Aβ has been long considered a leading hypothesis in the disease pathology, it is increasingly evident that the role hyperphosphorylation of tau in destabilization of microtubule assembly and disturbance of axonal transport is equally detrimental in the neurodegenerative process. The main kinase involved in phosphorylation of tau is glycogen-synthase kinase 3-beta (GSK-3β). Intracellular accumulation of Aβ also likely induces increase in hyperphosphorylated tau by a mechanism dependent on GSK-3β. In addition, Aβ affects production of ceramides, the major sphingolipids in mammalian cells, by acting on sphingomyelinases, enzymes responsible for the catabolic formation of ceramides from the sphingomyelin. Generated ceramides in turn increase production of Aβ by acting on β-secretase, a key enzyme in the proteolytic processing of the amyloid precursor protein (APP), altogether leading to a ceramide-Aβ-hyperphosphorylated tau cascade that ends in neuronal death. Modulators and inhibitors acting on members of this devastating cascade are considered as potential targets for AD therapy. There is still no adequate treatment for AD patients. Novel therapeutic strategies increasingly consider the combination of multiple targets and interactions among the key members of implicated molecular pathways. This review summarizes recent findings and therapeutic perspectives in the pathology and treatment of AD, with the emphasis on the interplay between hyperphosphorylated tau, amyloid β, and sphingolipid mediators.

scholarly journals Non-Alkaloid Cholinesterase Inhibitory Compounds from Natural Sources

Molecules ◽  
2021 ◽  
Vol 26 (18) ◽  
pp. 5582
Author(s):  
Alfred Ngenge Tamfu ◽  
Selcuk Kucukaydin ◽  
Balakyz Yeskaliyeva ◽  
Mehmet Ozturk ◽  
Rodica Mihaela Dinica
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cholinesterase Inhibitors ◽  
High Efficiency ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
New Drugs ◽  
Cholinesterase Inhibition ◽  
Natural Sources ◽  
Long Term Treatment

Alzheimer’s disease (AD) is a severe neurodegenerative disorder of different brain regions accompanied by distresses and affecting more than 25 million people in the world. This progressive brain deterioration affects the central nervous system and has negative impacts on a patient’s daily activities such as memory impairment. The most important challenge concerning AD is the development of new drugs for long-term treatment or prevention, with lesser side effects and greater efficiency as cholinesterases inhibitors and the ability to remove amyloid-beta(Aβ) deposits and other related AD neuropathologies. Natural sources provide promising alternatives to synthetic cholinesterase inhibitors and many have been reported for alkaloids while neglecting other classes with potential cholinesterase inhibition. This review summarizes information about the therapeutic potential of small natural molecules from medicinal herbs, belonging to terpenoids, coumarins, and phenolic compounds, and others, which have gained special attention due to their specific modes of action and their advantages of low toxicity and high efficiency in the treatment of AD. Some show superior drug-like features in comparison to synthetic cholinesterase inhibitors. We expect that the listed phytoconstituents in this review will serve as promising tools and chemical scaffolds for the discovery of new potent therapeutic leads for the amelioration and treatment of Alzheimer’s disease.

Exploring the Anti-Neuroinflammatory Potential of Steroid and Terpenoid-Derived Phytochemicals to Combat Alzheimer's Disease

2021 ◽  
Vol 26 ◽  
Author(s):  
Md. Tanvir Kabir ◽  
Md. Sahab Uddin ◽  
Sonia Zaman ◽  
Md. Sohanur Rahman ◽  
Tapan Behl ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Symptomatic Treatment ◽  
Drug Candidates ◽  
Age Related ◽  
Inflammatory Processes ◽  
Pharmacologically Active ◽  
And Behavior ◽  
Therapeutic Activities

: Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder that significantly affects cognitive functions in a way that causes loss of memory, thinking, and behavior. Multiple studies revealed that neuroinflammation associated with AD is linked with the amyloid-beta deposition in the brain. Elevated levels of expression of cytokines, microglial activation, nuclear factor kappa B, and reactive oxygen species play roles in ADrelated inflammatory processes. Indeed, effective therapeutic approaches are urgently required to develop therapeutic agents to prevent and treat AD. So far, many anti-AD drug candidates have failed in the clinical stages and currently available drugs only provide symptomatic treatment. In recent times, pharmacologically active phytochemicals have been found to possess promising anti-neuroinflammatory effects; therefore these natural products can be useful in the AD treatment. In this review, we have comprehensively discussed the role of neuroinflammation and the molecular processes altered by multiple steroid and terpenoid-derived phytochemicals in various AD-related neuroinflammatory pathways. Indeed, steroid and terpenoid-derived phytochemicals show important therapeutic activities, which can be useful in ameliorating and treating AD-related neurodegeneration.

Role of natural plant products against Alzheimer’s disease

2021 ◽  
Vol 20 ◽  
Author(s):  
Himanshi Varshney ◽  
Yasir Hasan Siddique
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Cholinesterase Inhibitors ◽  
Amyloid Fibrils ◽  
Therapeutic Agent ◽  
Neurodegenerative Disorder ◽  
Natural Plant ◽  
Plant Products

: Alzheimer’s disease (AD) is one of the major neurodegenerative disorder. Deposition of amyloid fibrils and tau protein are associated with various pathological symptoms. Currently limited medication is available for AD treatment. Most of the drugs are basically cholinesterase inhibitors and associated with various side effects. Natural plant products have shown potential as a therapeutic agent for the treatment of AD symptoms. Variety of secondary metabolites like flavonoids, tannins, terpenoids, alkaloids and phenols are used to reduce the progression of the disease. Plant products have less or no side effect and are easily available. The present review gives a detailed account of the potential of natural plant products against the AD symptoms.

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