Pharmacological targeting of MCL-1 promotes mitophagy and improves disease pathologies in an Alzheimer's disease mouse model.
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ABSTRACT:
SUBMITTER: Cen X
PROVIDER: S-EPMC7665171 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alzheimer's disease is characterized by two primary pathological features: amyloid plaques and neurofibrillary tangles. The interconnection between amyloid and tau aggregates is of intense interest, but mouse models have yet to reveal a direct interrelationship. We now show that NO may be a key factor that connects amyloid and tau pathologies. Genetic removal of NO synthase 2 in mice expressing mutated amyloid precursor protein results in pathological hyperphosphorylation of mouse tau, its redistribution to the somatodendritic compartment in cortical and hippocampal neurons, and aggregate formation. Lack of NO synthase 2 in the amyloid precursor protein Swedish mutant mouse increased insoluble beta-amyloid peptide levels, neuronal degeneration, caspase-3 activation, and tau cleavage, suggesting that NO acts at a junction point between beta-amyloid peptides, caspase activation, and tau aggregation.
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Project description:Currently, no effective therapeutics exist for the treatment of incurable neurodegenerative diseases such as Alzheimer's disease (AD). The cellular prion protein (PrPC) acts as a high-affinity receptor for amyloid beta oligomers (AβO), a main neurotoxic species mediating AD pathology. The interaction of AβO with PrPC subsequently activates Fyn tyrosine kinase and neuroinflammation. Herein, we used our previously developed peptide aptamer 8 (PA8) binding to PrPC as a therapeutic to target the AβO-PrP-Fyn axis and prevent its associated pathologies. Our in vitro results indicated that PA8 prevents the binding of AβO with PrPC and reduces AβO-induced neurotoxicity in mouse neuroblastoma N2a cells and primary hippocampal neurons. Next, we performed in vivo experiments using the transgenic 5XFAD mouse model of AD. The 5XFAD mice were treated with PA8 and its scaffold protein thioredoxin A (Trx) at a 14.4 µg/day dosage for 12 weeks by intraventricular infusion through Alzet® osmotic pumps. We observed that treatment with PA8 improves learning and memory functions of 5XFAD mice as compared to Trx-treated 5XFAD mice. We found that PA8 treatment significantly reduces AβO levels and Aβ plaques in the brain tissue of 5XFAD mice. Interestingly, PA8 significantly reduces AβO-PrP interaction and its downstream signaling such as phosphorylation of Fyn kinase, reactive gliosis as well as apoptotic neurodegeneration in the 5XFAD mice compared to Trx-treated 5XFAD mice. Collectively, our results demonstrate that treatment with PA8 targeting the AβO-PrP-Fyn axis is a promising and novel approach to prevent and treat AD.
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Project description:BackgroundCurrently, there is no cure for Alzheimer's disease (AD). Therapeutics that can modify the early stage of AD are urgently needed. Recent studies have shown that the pathogenesis of AD is closely regulated by an endo/lysosomal asparaginyl endopeptidase (AEP). Inhibition of AEP has been reported to prevent neural degeneration in transgenic mouse models of AD. However, more than 90% of AD cases are age-related sporadic AD rather than hereditary AD. The therapeutic efficacy of AEP inhibition in ageing-associated sporadic AD remains unknown.MethodsThe senescence-accelerated mouse prone 8 (SAMP8) was chosen as an approximate model of sporadic AD and treated with a selective AEP inhibitor,: δ-secretase inhibitor 11. Activation of AEP was determined by enzymatic activity assay. Concentration of soluble amyloid β (Aβ) in the brain was determined by ELISA. Morris water maze test was performed to assess the learning and memory-related cognitive ability. Pathological changes in the brain were explored by morphological and western blot analyses.ResultsThe enzymatic activity of AEP in the SAMP8 mouse brain was significantly higher than that in the age-matched SAMR1 mice. The half maximal inhibitory concentration (IC50) for δ-secretase inhibitor 11 to inhibit AEP in vitro is was around 150 nM. Chronic treatment with δ-secretase inhibitor 11 markedly decreased the brain AEP activity, reduced the generation of Aβ1-40/42 and ameliorated memory loss. The inhibition of AEP with this reagent not only reduced the AEP-cleaved tau fragments and tau hyperphosphorylation, but also attenuated neuroinflammation in the form of microglial activation. Moreover, treatment with δ-secretase inhibitor 11 prevented the synaptic loss and alleviated dendritic disruption in SAMP8 mouse brain.ConclusionsPharmacological inhibition of AEP can intervene and prevent AD-like pathological progress in the model of sporadic AD. The up-regulated AEP in the brain could be a promising target for early treatment of AD. The δ-secretase inhibitor 11 can be used as a lead compound for translational development of AD treatment.
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Project description:Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet the precise mechanisms underlying their effects on neuropathology remain unclear. To further define the influence of microglia on AD neuropathology, we generated a novel mouse model of AD that genetically lack microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid plaques to cerebral amyloid angiopathy (CAA) that is further accompanied by transcriptional changes within multiple cell types, a dramatic induction of brain calcification and cerebral hemorrhages, and premature lethality. Importantly, adult microglia replacement fully rescues these comorbidities, supporting novel roles for microglia in maintaining vascular function and preventing brain calcification. We further examined the clinical implications of these findings in human tissue and hiPSC-derived microglia, finding evidence that calcification is inversely related to plaque pathology and that microglial interactions with calcifications are altered by genetic AD risk factors.
2021-11-24 | GSE189033 | GEO
Project description:BackgroundAlzheimer's disease (AD) is a multifactorial disease, implying that multi-target treatments may be necessary to effectively cure AD. Tetrahydrobiopterin (BH4) is an enzymatic cofactor required for the synthesis of monoamines and nitric oxide that also exerts antioxidant and anti-inflammatory effects. Despite its crucial role in the CNS, the potential of BH4 as a treatment in AD has never been scrutinized.ObjectiveHere, we investigated whether BH4 peripheral administration improves cognitive symptoms and AD neuropathology in the triple-transgenic mouse model of AD (3xTg-AD), a model of age-related tau and amyloid-β (Aβ) neuropathologies associated with behavior impairment.MethodsNon-transgenic (NonTg) and 3xTg-AD mice were subjected to a control diet (5% fat - CD) or to a high-fat diet (35% fat - HFD) from 6 to 13 months to exacerbate metabolic disorders. Then, mice received either BH4 (15 mg/kg/day, i.p.) or vehicle for ten consecutive days.ResultsThis sub-chronic administration of BH4 rescued memory impairment in 13-month-old 3xTg-AD mice, as determined using the novel object recognition test. Moreover, the HFD-induced glucose intolerance was completely reversed by the BH4 treatment in 3xTg-AD mice. However, the HFD or BH4 treatment had no significant impact on Aβ and tau neuropathologies.ConclusionOverall, our data suggest a potential benefit from BH4 administration against AD cognitive and metabolic deficits accentuated by HFD consumption in 3xTg-AD mice, without altering classical neuropathology. Therefore, BH4 should be considered as a candidate for drug repurposing, at least in subtypes of cognitively impaired patients experiencing metabolic disorders.
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Project description:Compromised cellular energy metabolism, cerebral hypoperfusion, and neuronal calcium dysregulation are involved in the pathological process of Alzheimer's disease (AD). ATP-sensitive potassium (KATP) channels in plasma membrane and inner mitochondrial membrane play important roles in modulating neuronal excitability, cell survival, and cerebral vascular tone. To investigate the therapeutic potential of drugs that activate KATP channels in AD, we first characterized the effects of the KATP channel opener diazoxide on cultured neurons, and then determined its ability to modify the disease process in the 3xTgAD mouse model of AD. Plasma and mitochondrial membrane potentials, cell excitability, intracellular Ca2+ levels and bioenergetics were measured in cultured cerebral cortical neurons exposed to diazoxide. Diazoxide hyperpolarized neurons, reduced the frequency of action potentials, attenuated Ca2+ influx through NMDA receptor channels, and reduced oxidative stress. 3xTgAD mice treated with diazoxide for 8 months exhibited improved performance in a learning and memory test, reduced levels of anxiety, decreased accumulation of A? oligomers and hyperphosphorylated tau in the cortex and hippocampus, and increased cerebral blood flow. Our findings show that diazoxide can ameliorate molecular, cytopathological, and behavioral alterations in a mouse model of AD suggesting a therapeutic potential for drugs that activate KATP channels in the treatment of AD.
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