The Protective Mechanism of SIRT1 in the Regulation of Mitochondrial Biogenesis and Mitochondrial Autophagy in Alzheimer’s Disease

Silent information-regulated transcription factor 1 (SIRT1) is the most prominent and widely studied member of the sirtuins (a family of mammalian class III histone deacetylases). It is a nuclear protein, and the deacetylation of the peroxisome proliferator-activated receptor coactivator-1 has been extensively implicated in metabolic control and mitochondrial biogenesis and is the basis for studies into its involvement in caloric restriction and its effects on lifespan. The present study discusses the potentially protective mechanism of SIRT1 in the regulation of the mitochondrial biogenesis and autophagy involved in the modulation of Alzheimer’s disease, which may be correlated with the role of SIRT1 in affecting neuronal morphology, learning, and memory during development; regulating metabolism; counteracting stress responses; and maintaining genomic stability. Drugs that activate SIRT1 may offer a promising approach to treating Alzheimer’s disease

A Tale of Two Diseases: Exploring Mechanisms Linking Diabetes Mellitus with Alzheimer’s Disease

Journal of Alzheimer s Disease ◽

10.3233/jad-210612 ◽

2021 ◽

pp. 1-17

Author(s):

Jessica Lynn ◽

Mingi Park ◽

Christiana Ogunwale ◽

George K. Acquaah-Mensah

Keyword(s):

Diabetes Mellitus ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Glycogen Synthase ◽

Mammalian Target Of Rapamycin ◽

Insulin Receptors ◽

Peroxisome Proliferator ◽

Main Component ◽

The Impact

Dementias, including the type associated with Alzheimer’s disease (AD), are on the rise worldwide. Similarly, type 2 diabetes mellitus (T2DM) is one of the most prevalent chronic diseases globally. Although mechanisms and treatments are well-established for T2DM, there remains much to be discovered. Recent research efforts have further investigated factors involved in the etiology of AD. Previously perceived to be unrelated diseases, commonalities between T2DM and AD have more recently been observed. As a result, AD has been labeled as “type 3 diabetes”. In this review, we detail the shared processes that contribute to these two diseases. Insulin resistance, the main component of the pathogenesis of T2DM, is also present in AD, causing impaired brain glucose metabolism, neurodegeneration, and cognitive impairment. Dysregulation of insulin receptors and components of the insulin signaling pathway, including protein kinase B, glycogen synthase kinase 3β, and mammalian target of rapamycin are reported in both diseases. T2DM and AD also show evidence of inflammation, oxidative stress, mitochondrial dysfunction, advanced glycation end products, and amyloid deposition. The impact that changes in neurovascular structure and genetics have on the development of these conditions is also being examined. With the discovery of factors contributing to AD, innovative treatment approaches are being explored. Investigators are evaluating the efficacy of various T2DM medications for possible use in AD, including but not limited to glucagon-like peptide-1 receptor agonists, and peroxisome proliferator-activated receptor-gamma agonists. Furthermore, there are 136 active trials involving 121 therapeutic agents targeting novel AD biomarkers. With these efforts, we are one step closer to alleviating the ravaging impact of AD on our communities.

Signaling Mechanisms of Selective PPARγ Modulators in Alzheimer’s Disease

PPAR Research ◽

10.1155/2018/2010675 ◽

2018 ◽

Vol 2018 ◽

pp. 1-20 ◽

Cited By ~ 18

Author(s):

Manoj Govindarajulu ◽

Priyanka D. Pinky ◽

Jenna Bloemer ◽

Nila Ghanei ◽

Vishnu Suppiramaniam ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adverse Effects ◽

Therapeutic Potential ◽

Protein Accumulation ◽

Peroxisome Proliferator ◽

Continuous Increase ◽

Therapeutic Benefits ◽

The Brain

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by abnormal protein accumulation, synaptic dysfunction, and cognitive impairment. The continuous increase in the incidence of AD with the aged population and mortality rate indicates the urgent need for establishing novel molecular targets for therapeutic potential. Peroxisome proliferator-activated receptor gamma (PPARγ) agonists such as rosiglitazone and pioglitazone reduce amyloid and tau pathologies, inhibit neuroinflammation, and improve memory impairments in several rodent models and in humans with mild-to-moderate AD. However, these agonists display poor blood brain barrier permeability resulting in inadequate bioavailability in the brain and thus requiring high dosing with chronic time frames. Furthermore, these dosing levels are associated with several adverse effects including increased incidence of weight gain, liver abnormalities, and heart failure. Therefore, there is a need for identifying novel compounds which target PPARγ more selectively in the brain and could provide therapeutic benefits without a high incidence of adverse effects. This review focuses on how PPARγ agonists influence various pathologies in AD with emphasis on development of novel selective PPARγ modulators.

Chenodeoxycholic Acid Ameliorates AlCl3-Induced Alzheimer’s Disease Neurotoxicity and Cognitive Deterioration via Enhanced Insulin Signaling in Rats

Molecules ◽

10.3390/molecules24101992 ◽

2019 ◽

Vol 24 (10) ◽

pp. 1992 ◽

Cited By ~ 10

Author(s):

Firas H. Bazzari ◽

Dalaal M. Abdallah ◽

Hanan S. El-Abhar

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Chenodeoxycholic Acid ◽

Insulin Signaling ◽

Glucose Transporter ◽

Farnesoid X Receptor ◽

Peroxisome Proliferator ◽

Significant Difference

Insulin resistance is a major risk factor for Alzheimer’s disease (AD). Chenodeoxycholic acid (CDCA) and synthetic Farnesoid X receptor (FXR) ligands have shown promising outcomes in ameliorating insulin resistance associated with various medical conditions. This study aimed to investigate whether CDCA treatment has any potential in AD management through improving insulin signaling. Adult male Wistar rats were randomly allocated into three groups and treated for six consecutive weeks; control (vehicle), AD-model (AlCl3 50 mg/kg/day i.p) and CDCA-treated group (AlCl3 + CDCA 90 mg/kg/day p.o from day 15). CDCA improved cognition as assessed by Morris Water Maze and Y-maze tests and preserved normal histological features. Moreover, CDCA lowered hippocampal beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and amyloid-beta 42 (Aβ42). Although no significant difference was observed in hippocampal insulin level, CDCA reduced insulin receptor substrate-1 phosphorylation at serine-307 (pSer307-IRS1), while increased protein kinase B (Akt) activation, glucose transporter type 4 (GLUT4), peroxisome proliferator-activated receptor gamma (PPARγ) and glucagon-like peptide-1 (GLP-1). Additionally, CDCA activated cAMP response element-binding protein (CREB) and enhanced brain-derived neurotrophic factor (BDNF). Ultimately, CDCA was able to improve insulin sensitivity in the hippocampi of AlCl3-treated rats, which highlights its potential in AD management.

Roles of Cannabidiol in the treatment and prevention of Alzheimer’s disease by multi-target actions

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210331162857 ◽

2021 ◽

Vol 21 ◽

Author(s):

Xiao- Bei Zhang ◽

Jintao Li ◽

Juanhua Gu ◽

Yue-Qin Zeng

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transient Receptor Potential ◽

Senile Plaques ◽

Memory Loss ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Peroxisome Proliferator ◽

Protective Effects ◽

: Alzheimer’s disease (AD) is one of the most common neurodegenerative diseases with chronic, progressive, and irreversible characteristics, affecting nearly 50 million older adults worldwide. The pathogenesis of AD includes the formation of senile plaques, the abnormal aggregation of tau protein and the gradual degeneration and death of cerebral cortical cells. The main symptoms are memory loss, cognitive decline and behavioral disorders. Studies indicate that cannabidiol(CBD) possesses various pharmacological activities including anti-inflammatory, anti-oxidation and neuroprotective activities. It has been suggested as a potential multi-target medicine for treatment of AD. In this review, we aim to summarize the underlying mechanisms and protective effects of CBD on signaling pathways and central receptors involved in the pathogenesis of AD, including the endocannabinoid system（eCBs）, the Transient receptor potential vanilloid type 1(TRPV1) receptor, and the Peroxisome proliferator-activated receptor (PPAR) receptor.

PPARγ-coactivator-1α gene transfer reduces neuronal loss and amyloid-β generation by reducing β-secretase in an Alzheimer’s disease model

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1606171113 ◽

2016 ◽

Vol 113 (43) ◽

pp. 12292-12297 ◽

Cited By ~ 46

Author(s):

Loukia Katsouri ◽

Yau M. Lim ◽

Katrin Blondrath ◽

Ioanna Eleftheriadou ◽

Laura Lombardero ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Pyramidal Neurons ◽

Lentiviral Vector ◽

Disease Model ◽

Amyloid Β ◽

Neuronal Loss ◽

Peroxisome Proliferator ◽

Neuroprotective Effects ◽

Current therapies for Alzheimer’s disease (AD) are symptomatic and do not target the underlying Aβ pathology and other important hallmarks including neuronal loss. PPARγ-coactivator-1α (PGC-1α) is a cofactor for transcription factors including the peroxisome proliferator-activated receptor-γ (PPARγ), and it is involved in the regulation of metabolic genes, oxidative phosphorylation, and mitochondrial biogenesis. We previously reported that PGC-1α also regulates the transcription of β-APP cleaving enzyme (BACE1), the main enzyme involved in Aβ generation, and its expression is decreased in AD patients. We aimed to explore the potential therapeutic effect of PGC-1α by generating a lentiviral vector to express human PGC-1α and target it by stereotaxic delivery to hippocampus and cortex of APP23 transgenic mice at the preclinical stage of the disease. Four months after injection, APP23 mice treated with hPGC-1α showed improved spatial and recognition memory concomitant with a significant reduction in Aβ deposition, associated with a decrease in BACE1 expression. hPGC-1α overexpression attenuated the levels of proinflammatory cytokines and microglial activation. This effect was accompanied by a marked preservation of pyramidal neurons in the CA3 area and increased expression of neurotrophic factors. The neuroprotective effects were secondary to a reduction in Aβ pathology and neuroinflammation, because wild-type mice receiving the same treatment were unaffected. These results suggest that the selective induction of PGC-1α gene in specific areas of the brain is effective in targeting AD-related neurodegeneration and holds potential as therapeutic intervention for this disease.

Increased Expression of Cyclooxygenases and Peroxisome Proliferator-Activated Receptor-γ in Alzheimer's Disease Brains

Biochemical and Biophysical Research Communications ◽

10.1006/bbrc.1998.9981 ◽

1999 ◽

Vol 254 (3) ◽

pp. 582-586 ◽

Cited By ~ 130

Author(s):

Yoshihisa Kitamura ◽

Shun Shimohama ◽

Hideyasu Koike ◽

Jun-ichi Kakimura ◽

Yasuji Matsuoka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Peroxisome Proliferator ◽

The PPAR-γAgonist 15-Deoxy-Δ12,14-ProstaglandinJ2Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer's Disease

PPAR Research ◽

10.1155/2008/349185 ◽

2008 ◽

Vol 2008 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Jihong Xu ◽

Steven W. Barger ◽

Paul D. Drew

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Th17 Cells ◽

Human Subjects ◽

T Cell Response ◽

Great Promise ◽

Peroxisome Proliferator ◽

Cns Inflammation ◽

Synergistic Induction

Accumulation of amyloid-βpeptide (Aβ) appears to contribute to the pathogenesis of Alzheimer's disease (AD). Therapeutic hope for the prevention or removal of Aβdeposits has been placed in strategies involving immunization against the Aβpeptide. Initial Aβimmunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically,CD4+Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβimmunization in the treatment of AD. Interleukin (IL)-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR)-γagonist 15-deoxy-Δ12,14-PGJ2(15d-PGJ2) effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γagonists may be effective in modulating the development of AD.

Activation of the mTORC1/PGC-1 axis promotes mitochondrial biogenesis and induces cellular senescence in the lung epithelium

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00244.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. L1049-L1060 ◽

Cited By ~ 16

Author(s):

Ross Summer ◽

Hoora Shaghaghi ◽

DeLeila Schriner ◽

Willy Roque ◽

Dominic Sales ◽

...

Keyword(s):

Epithelial Cells ◽

Cellular Senescence ◽

Mitochondrial Biogenesis ◽

Lung Epithelial Cells ◽

Chronic Obstructive ◽

Protective Mechanism ◽

Peroxisome Proliferator ◽

Lung Epithelium ◽

Lung Epithelial

Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mammalian target of rapamycin/peroxisome proliferator-activated receptor-γ complex 1α/β (mTOR/PGC-1α/β) axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway is associated with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation, and augmented mitochondrial reactive oxygen species (ROS) production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC-1α/β axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.