Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress

Sang, Zhipei; Wang, Keren; Dong, Jianghong; Tang, Lei

doi:10.1016/j.ejmech.2022.114464

Cited by 67 publications

(36 citation statements)

References 202 publications

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“…Table 6 shows that the most studied neurological diseases are AD, TSC, and depression. AD is a chronic and progressive neurodegenerative disease of the brain and currently has no effective treatment ( Sang et al, 2022 ). TSC is an autosomal dominant disorder that can cause disabling neurological disorders, such as epilepsy and TSC-related neuropsychiatric disorders ( Luo et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Xia

Luo

et al. 2022

Front. Integr. Neurosci.

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Mammalian target of rapamycin (mTOR) is an important molecule that regulates cell metabolism, growth, and proliferation in the nervous system. This study aimed to present the current study hot spots and predict the future development trend of the mTOR pathway in neurologic diseases using bibliometrics. We referred to the publications in the Web of Science Core Collection database. VOSviewer and CiteSpace programs were used to evaluate countries/regions, institutions, authors, journals, keywords, and citations showing the current study focus and predicting the future trend of mTOR in neuroscience. The search date ended on 19 June 2022, and there were 3,029 articles on mTOR in neuroscience from 2002 to 2021. Visual analysis showed that although the number of publications declined slightly in some years, the number of publications related to mTOR generally showed an upward trend, reaching its peak in 2021. It had the largest number of publications in the United States. Keywords and literature analysis showed that protein synthesis regulation, ischemia, mitochondrial dysfunction, oxidative stress, and neuroinflammation may be hot spots and future directions of the nervous system in mTOR studies. Recently, the most studied neurological diseases are Alzheimer’s disease (AD), tuberous sclerosis complex (TSC), and depression, which are still worthy of further studies by researchers in the future. This can provide a useful reference for future researchers to study mTOR further in the field of neuroscience.

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Section: Discussionmentioning

confidence: 99%

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Xia

Luo

et al. 2022

Front. Integr. Neurosci.

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“…The multitarget-directed ligand (MTDL) approach is frequently used in the development of new AD drugs. Newly tested MTDLs affect various pathways involved in the development of AD, mainly focusing on reducing cholinergic depletion, glutamate toxicity, Aβ aggregation, tau hyperphosphorylation, and oxidative stress [ 342 , 343 , 344 , 345 , 346 ]. For example, ladostigil, which acts as a reversible cholinesterase inhibitor and an irreversible MAO-B inhibitor, has entered clinical trials; it has neuroprotective effects, increases the expression of neurotrophic factors, induces neurogenesis, and has antidepressant effects [ 347 , 348 ].…”

Section: Alzheimer’s Drugsmentioning

confidence: 99%

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Fišar

2022

Biomolecules

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Damage or loss of brain cells and impaired neurochemistry, neurogenesis, and synaptic and nonsynaptic plasticity of the brain lead to dementia in neurodegenerative diseases, such as Alzheimer’s disease (AD). Injury to synapses and neurons and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles are considered the main morphological and neuropathological features of AD. Age, genetic and epigenetic factors, environmental stressors, and lifestyle contribute to the risk of AD onset and progression. These risk factors are associated with structural and functional changes in the brain, leading to cognitive decline. Biomarkers of AD reflect or cause specific changes in brain function, especially changes in pathways associated with neurotransmission, neuroinflammation, bioenergetics, apoptosis, and oxidative and nitrosative stress. Even in the initial stages, AD is associated with Aβ neurotoxicity, mitochondrial dysfunction, and tau neurotoxicity. The integrative amyloid-tau-mitochondrial hypothesis assumes that the primary cause of AD is the neurotoxicity of Aβ oligomers and tau oligomers, mitochondrial dysfunction, and their mutual synergy. For the development of new efficient AD drugs, targeting the elimination of neurotoxicity, mutual potentiation of effects, and unwanted protein interactions of risk factors and biomarkers (mainly Aβ oligomers, tau oligomers, and mitochondrial dysfunction) in the early stage of the disease seems promising.

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“…However, these drugs only have limited symptomatic relief but fail to prevent AD progression. Several newer molecules that have been identified for AD in the last four decades act by preventing amyloid deposition in the brain and removing existing amyloid plaques along with other recognized mechanisms associated with the disease . Although these compounds demonstrate promising data from preclinical AD models, the clinical failure rate in AD treatment is almost 100%.…”

Section: Introductionmentioning

confidence: 99%

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

et al. 2022

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A robust preclinical disease model is a primary requirement to understand the underlying mechanisms, signaling pathways, and drug screening for human diseases. Although various preclinical models are available for several diseases, clinical models for Alzheimer’s disease (AD) remain underdeveloped and inaccurate. The pathophysiology of AD mainly includes the presence of amyloid plaques and neurofibrillary tangles (NFT). Furthermore, neuroinflammation and free radical generation also contribute to AD. Currently, there is a wide gap in scientific approaches to preventing AD progression. Most of the available drugs are limited to symptomatic relief and improve deteriorating cognitive functions. To mimic the pathogenesis of human AD, animal models like 3XTg-AD and 5XFAD are the primarily used mice models in AD therapeutics. Animal models for AD include intracerebroventricular-streptozotocin (ICV-STZ), amyloid beta-induced, colchicine-induced, etc., focusing on parameters such as cognitive decline and dementia. Unfortunately, the translational rate of the potential drug candidates in clinical trials is poor due to limitations in imitating human AD pathology in animal models. Therefore, the available preclinical models possess a gap in AD modeling. This paper presents an outline that critically assesses the applicability and limitations of the current approaches in disease modeling for AD. Also, we attempted to provide key suggestions for the best-fit model to evaluate potential therapies, which might improve therapy translation from preclinical studies to patients with AD.

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Alzheimer's disease: Updated multi-targets therapeutics are in clinical and in progress

Cited by 67 publications

References 202 publications

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Linking the Amyloid, Tau, and Mitochondrial Hypotheses of Alzheimer’s Disease and Identifying Promising Drug Targets

Preclinical Models for Alzheimer’s Disease: Past, Present, and Future Approaches

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