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Data refers to reference modules obtained using gene expression only (expression), by integrating this information with SNPs (expression+SNPs), and by merging the mRNA expression data, SNPs and drug targets (expression+SNPs+drug targets), and by combining the mRNA expression data, SNPs, drug targets, and OMIM genes (expression +SNPs+drug targets+ OMIM). In light blue are GO terms associated to synaptic transmission and neuronal signaling, in dark green are metabolism-associated GO terms, in gray remaining relevant terms. Highlighted are the results which have been discussed in detail in the discussion section. Specific GO terms are described in Table S2.
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Alzheimer's disease is the most common cause of dementia worldwide, affecting the elderly population. It is characterized by the hallmark pathology of amyloid-β deposition, neurofibrillary tangle formation, and extensive neuronal degeneration in the brain. Wealth of data related to Alzheimer's disease has been generated to date, nevertheless, the m...
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Citations
... AMP-activated protein kinase (AMPK) is a critical effector to maintain energy homeostasis in cells and has recently been implicated in the pathogenesis of AD [11][12][13][14][15]. Specifically, over-activation of AMPK exacerbates Aβ-dependent dendritic spine loss and, consistently, inhibition of AMPK alleviates spine loss and rescues impairments of hippocampal synaptic plasticity and memory deficits associated with Aβ [14][15][16]. Also, dysregulation in cellular energy homeostasis has been recognized as a major defect in AD [12,17,18]. These findings have led to the hypothesis that AMPK and AMPK-related proteins, including the salt inducible kinases (SIK), may be implicated in the neuropathology of AD [19][20][21]. ...
... Because AMPK is a key regulator in cellular energy homeostasis and is implicated in metabolic impairments in AD [15,17], we wondered whether the AMPK-related member SIK1 is also involved in AD conditions. To this end, we immunoblotted for SIK1 in brain tissues from AD patients. ...
A reduction in AMPA receptor (AMPAR) expression and weakened synaptic activity is early cellular phenotypes in Alzheimer’s disease (AD). However, the molecular processes leading to AMPAR downregulation are complex and remain less clear. Here, we report that the salt inducible kinase SIK1 interacts with AMPARs, leading to a reduced accumulation of AMPARs at synapses. SIK1 protein level is sensitive to amyloid beta (Aβ) and shows a marked increase in the presence of Aβ and in AD brains. In neurons, Aβ incubation causes redistribution of SIK1 to synaptic sites and enhances SIK1-GluA1 association. SIK1 function is required for Aβ-induced AMPAR reduction. Importantly, in 3xTG AD mice, knockdown of SIK1 in the brain leads to restoration of AMPAR expression and a rescue of the cognitive deficits. These findings indicate an important role for SIK1 in meditating the cellular and functional pathology in AD.
... Our work also shows that OA triggers an increased activation of AMPK and of ERK1/2, both described to mediate the multilayered underlying pathologies of AD [113]. For instance, early studies demonstrate the abnormal activation of AMPK in postmortem AD brains, suggested to be also an upstream event in AD and other tauopathies [65], and a probable response to the impaired energy metabolism that characterizes AD [114], which are in agreement to our results and may reflect a response to OA-induced energetic crisis. Other studies report a co-localization between phosphorylated ERK1/2 and the initial stages of tau abnormal phosphorylation in AD brains [64], and its involvement on amyloid precursor protein (APP) and amyloid β (Aβ)-induced neurodegeneration in in vitro experiments [115]. ...
Alzheimer's disease (AD) research started several decades ago and despite the many efforts employed to develop new treatments or approaches to slow and/or revert disease progression, AD treatment remains an unsolved issue. Knowing that mitochondria loss of function is a central hub for many AD-associated pathophysiological processes, there has been renewed interest in exploring mitochondria as targets for intervention. In this perspective, the present study was aimed to investigate the possible beneficial effects of 2,4 dinitrophenol (DNP), a mitochondrial uncoupler agent, in an in vitro model of AD. Retinoic acid-induced differentiated SH-SY5Y cells were incubated with okadaic acid (OA), a neurotoxin often used as an AD experimental model, and/or with DNP. OA caused a decrease in neuronal cells viability, induced multiple mitochondrial anomalies including increased levels of reactive oxygen species, decreased bioenergetics and mitochondria content markers, and an altered mitochondria morphology. OA-treated cells also presented increased lipid peroxidation levels, and overactivation of tau related kinases (GSK3β, ERK1/2 and AMPK) alongside with a significant augment in tau protein phosphorylation levels. Interestingly, DNP co-treatment ameliorated and rescued OA-induced detrimental effects not only on mitochondria but also but also reinstated signaling pathways homeostasis and ameliorated tau pathology. Overall, our results show for the first time that DNP has the potential to preserve mitochondria homeostasis under a toxic insult, like OA exposure, as well as to reestablish cellular signaling homeostasis. These observations foster the idea that DNP, as a mitochondrial modulator, might represent a new avenue for treatment of AD.
... AMPK acts as an energy receptor and participates in many physiological processes like cell growth, metabolism, and apoptosis. Besides, it is a crucial factor affecting inflammation and insulin resistance associated with Alzheimer's pathology (8,9). Activating AMPK increases insulin sensitivity and inhibits hepatic gluconeogenesis, improving hyperglycemia. ...
Objective(s)
Metformin, as an insulin sensitizer, is a familiar antidiabetic drug. Increasing evidence points to metformin’s protective effects against Alzheimer’s disease (AD). However, the mechanism is not well understood. The present study evaluated whether inhibiting AMPK and activating mTOR could stop metformin from improving memory in rats with streptozotocin (STZ) -induced Alzheimer’s disease.
Materials and Methods
Twelve-week-old Wistar rats, were injected 3 mg/kg STZ intracerebroventricularly on days 1 and 3 to develop the animal model. Metformin was applied orally at 100 mg/kg (17 days). Forty-five min before the retrieval phase, dorsomorphin (DM; AMPK inhibitor, 2 M) and MHY (mTOR activator, 0.1 M) were administered. Morris Water Maze (MWM) and shuttle box were utilized to measure spatial and passive avoidance memory, respectively. Congo red staining was used to identify cortical amyloid deposition.
Results
The findings exhibited a considerable enhancement in spatial learning and memory in the metformin treatment group (P≤0.05). Injection of DM and MHY alone could not significantly change MWM and passive avoidance. Additionally, co-administration of DM and MHY increased escape latency (P≤0.001) and reduced the total time spent in the target quadrant (TTS) (P≤0.05) compared to the STZ+MET group during retrieval of MWM. Also, co-injection of DM and MHY increased step-through latency (STL) and decreased time spent in the dark compartment (TDC) compared to the STZ+MET group (P≤0.001).
Conclusion
Metformin appears to have a therapeutic impact by activating AMPK and inactivating mTOR. As a result, it could be used as an Alzheimer’s treatment strategy.
... One of them includes activation of AMPK that has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, and Aβ and pTau proteostasis (91)(92)(93). Combined analysis performed using multiple types of genome-wide association study (GWAS) data identified a predominant role for metabolism-associated biological processes in the course of AD, including autophagy, insulin and fatty acid metabolism, with a focus on AMPK as a key modulator and therapeutic target (94). Other include hormetic mechanisms such as sublethal ROS production that activates antioxidant response predisposing cells to a better reaction to stress (90). ...
Despite recent FDA approval of anti-amyloid antibodies for Alzheimer's Disease, strategies that target early molecular mechanisms and could delay or change the disease trajectory are still needed. Mitochondria emerge as a signaling organelle that could modulate multiple molecular mechanisms to enhance cellular bioenergetics and promote neuronal survival. Approaches to enhance mitochondrial function could promote healthy aging delaying the onset of age-related diseases such as Alzheimer's Disease. Some of these strategies have been recently tested in clinical trials. Emerging evidence demonstrates that in response to mild energetic stress, mitochondria could orchestrate a robust adaptive stress response activating multiple neuroprotective mechanism. The objective of this review is to highlight recent development of mitochondria-targeting therapeutics for neurodegenerative diseases, mitochondria complex I inhibitors in particular.
... damage. This is in accordance with Caberlotto et al. (2013) who reported that deregulation of energy homeostasis plays a key role in AD. Additionally, Assefa et al. (2020) reported that AMPK appears to link energy metabolism to synaptic plasticity and suggested that energy deficiency is linked to abnormalities in synaptic transmission and memory impairment. ...
Alzheimer’s disease (AD) is a worldwide chronic progressive neurodegenerative disease. We aimed to investigate and compare the neuroprotective impact of acetyl-l-carnitine and caloric restriction (CR) on AlCl3-induced AD to explore the pathogenesis and therapeutic strategies of AD. Sixty-seven adult male Wistar rats were allocated into Control, AlCl3, AlCl3–acetyl-l-carnitine, and AlCl3–CR groups. Each of AlCl3 and acetyl-l-carnitine were given by gavage in a daily dose of 100 mg/kg and CR was conducted by giving 70% of the daily average caloric intake of the control group. Rats were subjected to behavioral assessment using open field test, Y maze, novel object recognition test and passive avoidance test, biochemical assay of serum phosphorylated tau (pTau), hippocampal homogenate phosphorylated adenosine monophosphate-activated protein kinase, Beclin-1, Bcl-2-associated X protein, and B cell lymphoma 2 (Bcl2) as well as hippocampal Ki-67 and glial fibrillary acidic protein immunohistochemistry. AlCl3-induced cognitive and behavioral deficits coincident with impaired autophagy and enhanced apoptosis associated with defective neurogenesis and defective astrocyte activation. Acetyl-l-carnitine and CR partially protect against AlCl3-induced behavioral, cognitive, biochemical, and histological changes, with more ameliorative effect of acetyl-l-carnitine on hippocampal apoptotic markers, and more obvious behavioral and histological improvement with CR.
... Induced autophagy is conducive to the development of AD. Studies have shown that activation of mammalian target of rapamycin (mTOR, a regulator of cell growth and proliferation) inhibits the occurrence of autophagy, thus promoting the aggregation of Aβ and the formation of NFTs [96,97]. The normal metabolic process of the cell requires a continuous energy supply, and the mitochondria are the main location of oxidative phosphorylation and synthesis of ATP in the cell. ...
The pathogenesis and etiology of diabetes mellitus (DM) and Alzheimer’s disease (AD) share many common cellular and molecular themes. Recently, a growing body of research has shown that AMP-activated protein kinase (AMPK), a biomolecule that regulates energy balance and glucose and lipid metabolism, plays key roles in DM and AD. In this review, we summarize the relevant research on the roles of AMPK in DM and AD, including its functions in gluconeogenesis and insulin resistance (IR) and its relationships with amyloid β-protein (Aβ), Tau and AMPK activators. In DM, AMPK is involved in the regulation of glucose metabolism and IR. AMPK is closely related to gluconeogenesis, which can not only be activated by the upstream kinases liver kinase B1 (LKB1), transforming growth factor β-activated kinase 1 (TAK1), and Ca²⁺/calmodulin-dependent protein kinase kinase β (CaMKKβ) but also regulate the downstream kinases glucose-6-phosphatase (G-6-Pase) and phosphoenolpyruvate carboxy kinase (PEPCK), thereby affecting gluconeogenesis and ameliorating DM. Moreover, AMPK can regulate glucose transporter 4 (GLUT4) and free fatty acids to improve IR. In AD, AMPK can ameliorate abnormal brain energy metabolism, not only by reduces Aβ deposition through β-secretase but also reduces tau hyperphosphorylation through sirtuin 1 (SIRT1) and protein phosphatase 2A (PP2A). Therefore, AMPK is a bridge between DM and AD.
... Molecular mechanisms of mitochondria-mediated stress response mainly converge on the activation of the AMP-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis (Hardie et al., 2012;Weir et al., 2017). AMPK activation has been shown to engage multiple downstream pathways including mitochondrial biogenesis, autophagy, enhanced proteostasis (e.g., the removal of aggregated A and pTau proteins), improved antioxidant and anti-inflammatory response, ultimately leading to enhanced energy homeostasis, mitochondrial and cognitive function, and neuroprotection (Caberlotto et al., 2013;Gabuzda et al., 1994;Marinangeli et al., 2018). ...
Novel therapeutic strategies for Alzheimer’s disease (AD) are of the greatest priority given the consistent failure of recent clinical trials focused on Aβ or pTau. Earlier, we demonstrated that mild mitochondrial complex I inhibitor CP2 blocks neurodegeneration and cognitive decline in multiple mouse models of AD. To evaluate the safety of CP2 in humans, we performed a genome-wide association study (GWAS) using 196 lymphoblastoid cell lines and identified 11 SNP loci and 64 mRNA expression probe sets that potentially associate with CP2 susceptibility. Using primary mouse neurons and pharmacokinetic study, we show that CP2 is generally safe at a therapeutic dose.
... While mechanisms of the stress response are complex, AMP-activated protein kinase (AMPK)-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, Tau phosphorylation, and amyloidogenesis 10 . Combined analysis performed using multiple types of genome-wide data identified a predominant role for metabolism-associated biological processes in the course of AD, including autophagy and insulin and fatty acid metabolism, with a focus on AMPK as a key modulator and therapeutic target 11 . However, the development of direct pharmacological AMPK activators to elicit beneficial effects has presented multiple challenges 12 . ...
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration.
Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, 31P
NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
... While mechanisms of the stress response are complex, AMP-activated protein kinase (AMPK)-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, Tau phosphorylation, and amyloidogenesis 10 . Combined analysis performed using multiple types of genome-wide data identified a predominant role for metabolism-associated biological processes in the course of AD, including autophagy and insulin and fatty acid metabolism, with a focus on AMPK as a key modulator and therapeutic target 11 . However, the development of direct pharmacological AMPK activators to elicit beneficial effects has presented multiple challenges 12 . ...
Alzheimer’s Disease (AD) is a devastating neurodegenerative disorder without a cure. Here we show that mitochondrial respiratory chain complex I is an important small molecule druggable target in AD. Partial inhibition of complex I triggers the AMP-activated protein kinase-dependent signaling network leading to neuroprotection in symptomatic APP/PS1 female mice, a translational model of AD. Treatment of symptomatic APP/PS1 mice with complex I inhibitor improved energy homeostasis, synaptic activity, long-term potentiation, dendritic spine maturation, cognitive function and proteostasis, and reduced oxidative stress and inflammation in brain and periphery, ultimately blocking the ongoing neurodegeneration. Therapeutic efficacy in vivo was monitored using translational biomarkers FDG-PET, ³¹ P NMR, and metabolomics. Cross-validation of the mouse and the human transcriptomic data from the NIH Accelerating Medicines Partnership–AD database demonstrated that pathways improved by the treatment in APP/PS1 mice, including the immune system response and neurotransmission, represent mechanisms essential for therapeutic efficacy in AD patients.
... AMPK-mediated signaling has been directly linked to the regulation of cell metabolism, mitochondrial dynamics and function, inflammation, oxidative stress, protein turnover, tau phosphorylation, and amyloidogenesis [46]. Combined analysis performed using multiple types of genome-wide data identified a predominant role for metabolism-associated biological processes in the course of AD, including autophagy and insulin and fatty acid metabolism, with a focus on AMPK as a key modulator and therapeutic target [74]. While the molecular mechanisms associated with AMPK activation are complex and require further investigation, AMPK could reduce the activity of GSK3 via activation of Wnt signaling pathway [75]. ...
Background: Accumulation of hyperphosphorylated tau (pTau) protein is associated with synaptic dysfunction in Alzheimer's disease (AD). We previously demonstrated that neuroprotection in familial mouse models of AD could be achieved by targeting mitochondria complex I (MCI) and activating the adaptive stress response. Efficacy of this strategy on pTau-related pathology remained unknown. Objective: To investigate the effect of specific MCI inhibitor tricyclic pyrone compound CP2 on levels of human pTau, memory function, long term potentiation (LTP), and energy homeostasis in 18-month-old 3xTg-AD mice and explore the potential mechanisms. Methods: CP2 was administered to male and female 3xTg-AD mice from 3.5-18 months of age. Cognitive function was assessed using the Morris water maze. Glucose metabolism was measured in periphery using a glucose tolerance test and in the brain using fluorodeoxyglucose F18 positron-emission tomography (FDG-PET). LTP was evaluated using electrophysiology in the hippocampus. The expression of key proteins associated with neuroprotective mechanisms were assessed by western blotting. Results: Chronic CP2 treatment restored synaptic activity in female 3xTg-AD mice; cognitive function, levels of synap-tic proteins, glucose metabolism, and energy homeostasis were improved in male and female 3xTg-AD mice. Significant reduction of human pTau in the brain was associated with increased activity of protein phosphatase of type 2A (PP2A), and reduced activity of cyclin-dependent kinase 5 (CDK5) and glycogen synthase kinase 3 (GSK3). Conclusion: CP2 treatment protected against synaptic dysfunction and memory impairment in symptomatic 3xTg-AD mice, and reduced levels of human pTau, indicating that targeting mitochondria with small molecule specific MCI inhibitors represents a promising strategy for treating AD.
