Circadian clocks, cognition, and Alzheimer’s disease: synaptic mechanisms, signaling effectors, and chronotherapeutics DOI Creative Commons
Kari R. Hoyt, Karl Obrietan

Molecular Neurodegeneration, Journal Year: 2022, Volume and Issue: 17(1)

Published: May 7, 2022

Abstract Modulation of basic biochemical and physiological processes by the circadian timing system is now recognized as a fundamental feature all mammalian organ systems. Within central nervous system, these clock-modulating effects are reflected in some most complex behavioral states including learning, memory, mood. How clock shapes only beginning to be realized. In this review we describe recent findings regarding set cellular signaling events, kinase pathways, gene networks, synaptic circuits that under influence how this, turn, cognitive capacity over cycle. Further, discuss functional roles master located suprachiasmatic nucleus, peripheral oscillator populations within cortical limbic circuits, gating plasticity memory These then used basis connection between dysregulation impairments resulting from Alzheimer’s disease (AD). addition, conceptually novel idea AD, there selective disruption it disruption/desynchronization regions phase-entraining SCN underlies aspects early- mid-stage deficits AD. prospect AD could produce self-reinforcing feedback loop, where accelerates pathogenesis (e.g., amyloid deposition, oxidative stress cell death) turn leads further system. Lastly, address potential therapeutic approaches strengthen networks and, improve patients.

Language: Английский

Alzheimer's disease: Recent treatment strategies DOI
Miguel Vaz, Samuel Silvestre

European Journal of Pharmacology, Journal Year: 2020, Volume and Issue: 887, P. 173554 - 173554

Published: Sept. 14, 2020

Language: Английский

Citations

448
BACE1 inhibitors: Current status and future directions in treating Alzheimer's disease DOI Open Access

Nour M. Moussa‐Pacha,

Shifaa M. Abdin, Hany A. Omar

et al.

Medicinal Research Reviews, Journal Year: 2019, Volume and Issue: 40(1), P. 339 - 384

Published: July 26, 2019

Abstract Alzheimer's disease (AD) is an irreversible, progressive neurodegenerative brain disorder with no current cure. One of the important therapeutic approaches AD inhibition β‐site APP cleaving enzyme‐1 (BACE1), which involved in rate‐limiting step cleavage process amyloid precursor protein (APP) leading to generation neurotoxic β (Aβ) after γ‐secretase completes its function. The produced insoluble Aβ aggregates lead plaques deposition and neurodegeneration. BACE1 is, therefore, one attractive targets for treatment AD. This approach led development potent inhibitors, many were advanced late stages clinical trials. Nonetheless, high failure rate drug candidates targeting brought forefront need finding new uncover mystery behind In this review, we aim discuss most promising classes inhibitors a description analysis their pharmacodynamic pharmacokinetic parameters, more focus on that reached trials, such as MK8931, AZD‐3293, JNJ‐54861911, E2609, CNP520. addition, manuscript discusses safety concerns insignificant physiological effects, highlighted successful inhibitors. Furthermore, review demonstrates increasing evidence despite tremendous efforts results conceived latest studies suggest use treating should be reconsidered. Finally, sheds light alternative options

Language: Английский

Citations

251
A walk through tau therapeutic strategies DOI Creative Commons
Santosh Jadhav, Jesús Ávila, Michael Schöll

et al.

Acta Neuropathologica Communications, Journal Year: 2019, Volume and Issue: 7(1)

Published: Feb. 15, 2019

Tau neuronal and glial pathologies drive the clinical presentation of Alzheimer's disease related human tauopathies. There is a growing body evidence indicating that pathological tau species can travel from cell to spread pathology through brain. Throughout last decade, physiological have become attractive targets for AD therapies. Several therapeutic approaches been proposed, including inhibition protein kinases or protein-3-O-(N-acetyl-beta-D-glucosaminyl)-L-serine/threonine Nacetylglucosaminyl hydrolase, aggregation, active passive immunotherapies, silencing by antisense oligonucleotides. New therapeutics, across board, demonstrated ability prevent reduce lesions improve either cognitive motor impairment in variety animal models developing neurofibrillary pathology. The most advanced strategy treatment tauopathies remains immunotherapy, which has already reached stage drug development. vaccines humanised antibodies target intracellular extracellular spaces. Some them recognise amino-terminus carboxy-terminus, while others display binding abilities proline-rich area microtubule domains. main foci existing trials are on disease, progressive supranuclear palsy non-fluent primary aphasia. therapy offers new hope many fatal brain disorders. First efficacy data will be available end this decade.

Language: Английский

Citations

250
Dynamics of diabetes and obesity: Epidemiological perspective DOI Creative Commons

Annette Boles,

Ramesh Kandimalla, P. Hemachandra Reddy

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2017, Volume and Issue: 1863(5), P. 1026 - 1036

Published: Jan. 25, 2017

Language: Английский

Citations

242
Restoring Wnt/β-catenin signaling is a promising therapeutic strategy for Alzheimer’s disease DOI Creative Commons
Lin Jia, Juan C. Piña‐Crespo, Yonghe Li

et al.

Molecular Brain, Journal Year: 2019, Volume and Issue: 12(1)

Published: Dec. 1, 2019

Abstract Alzheimer’s disease (AD) is an aging-related neurological disorder characterized by synaptic loss and dementia. Wnt/β-catenin signaling essential signal transduction pathway that regulates numerous cellular processes including cell survival. In brain, not only crucial for neuronal survival neurogenesis, but it plays important roles in regulating plasticity blood-brain barrier integrity function. Moreover, activation of inhibits amyloid-β production tau protein hyperphosphorylation the brain. Critically, greatly suppressed AD brain via multiple pathogenic mechanisms. As such, restoring represents a unique opportunity rational design novel therapies.

Language: Английский

Citations

228
Memantine for the Treatment of Dementia: A Review on its Current and Future Applications DOI Open Access
Jaume Folch, Oriol Busquets, Miren Ettcheto

et al.

Journal of Alzheimer s Disease, Journal Year: 2017, Volume and Issue: 62(3), P. 1223 - 1240

Published: Dec. 15, 2017

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning memory. An excessive activation NMDARs has been associated with neuronal loss. discovery extrasynaptic provided rational physiological explanation between excitotoxic actions glutamate. Memantine (MEM), an antagonist NMDAR, currently used treatment AD jointly acetylcholinesterase inhibitors. It demonstrated that MEM preferentially prevents continuous NMDAR therefore cell death induced excitotoxicity without disrupting synaptic activity. problem shown no clear positive effects clinical applications while, preclinical stages, had very promising results. data studies suggests impact on improving neuropathology, as well preventing Aβ production, aggregation, or downstream neurotoxic consequences, part through blockade NMDAR. Thus, focus this review primarily to discuss efficacy models AD, consider possible combinations drug others, then evaluate reasons its lack trials. Finally, other pathologies also considered.

Language: Английский

Citations

205
Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease DOI Open Access
Teeba Athar,

Khalid Al Balushi,

Shah Alam Khan

et al.

Molecular Biology Reports, Journal Year: 2021, Volume and Issue: 48(7), P. 5629 - 5645

Published: June 28, 2021

Language: Английский

Citations

189
Neuroinflammation and Neurogenesis in Alzheimer’s Disease and Potential Therapeutic Approaches DOI Open Access
Pi‐Shan Sung, Po‐Yu Lin, Chi‐Hung Liu

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(3), P. 701 - 701

Published: Jan. 21, 2020

In adult brain, new neurons are generated throughout adulthood in the subventricular zone and dentate gyrus; this process is commonly known as neurogenesis. The regulation or modulation of neurogenesis includes various intrinsic pathways (signal transduction pathway epigenetic genetic pathways) extrinsic (metabolic growth factor modulation, vascular, immune system pathways). Altered has been identified Alzheimer's disease (AD), both human AD brains rodent models. exact mechanism dysregulation not completely elucidated. However, neuroinflammation demonstrated to alter presence inflammatory components, such cells, cytokines, chemokines, plays a role regulating survival, proliferation, maturation neural stem cells. Neuroinflammation also considered hallmark neuropathological feature AD. review, we summarize current, state-of-the art perspectives on neurogenesis, neuroinflammation, relationship between these two phenomena Furthermore, discuss potential therapeutic approaches, focusing anti-inflammatory proneurogenic interventions that have reported field.

Language: Английский

Citations

159
Glycogen synthesis and beyond, a comprehensive review of GSK3 as a key regulator of metabolic pathways and a therapeutic target for treating metabolic diseases DOI
Li Wang, Jiajia Li,

Li‐jun Di

et al.

Medicinal Research Reviews, Journal Year: 2021, Volume and Issue: 42(2), P. 946 - 982

Published: Nov. 3, 2021

Abstract Glycogen synthase kinase‐3 (GSK3) is a highly evolutionarily conserved serine/threonine protein kinase first identified as an enzyme that regulates glycogen (GS) in response to insulin stimulation, which involves GSK3 regulation of glucose metabolism and energy homeostasis. Both isoforms GSK3, GSK3α, GSK3β, have been implicated many biological pathophysiological processes. The various functions are indicated by its widespread distribution multiple cell types tissues. studies activity using animal models the observed effects GSK3‐specific inhibitors provide more insights into roles regulating cross‐talk between some important regulators sensors mitochondrial component function further highlight molecular mechanisms involved regulate metabolic activity, beyond classical regulatory effect on GS. In this review, we summarize specific tissues tightly associated with development disorders. We also address impacts function, regulation. application clinical tests will be highlighted too. Interactions GSK3‐mediated responses different stresses related described brief overview previously less‐appreciated diseases through GS other functions.

Language: Английский

Citations

130
Potential and Therapeutic Roles of Diosmin in Human Diseases DOI Creative Commons
Etimad Huwait, Mohammad Mobashir

Biomedicines, Journal Year: 2022, Volume and Issue: 10(5), P. 1076 - 1076

Published: May 6, 2022

Because of their medicinal characteristics, effectiveness, and importance, plant-derived flavonoids have been a possible subject research for many years, particularly in the last decade. Plants contain huge number flavonoids, Diosmin, flavone glycoside, is one them. Numerous

Language: Английский

Citations

93