scholarly journals The Role of PGC1α in Alzheimer’s Disease and Therapeutic Interventions

2021 ◽  
Vol 22 (11) ◽  
pp. 5769
Author(s):  
Bibiana C. Mota ◽  
Magdalena Sastre
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Amyloid Β ◽  
Therapeutic Interventions ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Aβ Generation ◽  
Therapy Studies

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer’s disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.

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

2016 ◽  
Vol 113 (43) ◽  
pp. 12292-12297 ◽  
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 ◽  
Peroxisome Proliferator Activated Receptor

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.

scholarly journals Alzheimer’s Disease, a Lipid Story: Involvement of Peroxisome Proliferator-Activated Receptor α

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1215 ◽  
Author(s):  
Francisco Sáez-Orellana ◽  
Jean-Noël Octave ◽  
Nathalie Pierrot
Keyword(s):  
Risk Factors ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Amyloid Β ◽  
The Elderly ◽  
Special Focus ◽  
Peroxisome Proliferator ◽  
Amyloid Β Peptide ◽  
Peroxisome Proliferator Activated Receptor

Alzheimer’s disease (AD) is the leading cause of dementia in the elderly. Mutations in genes encoding proteins involved in amyloid-β peptide (Aβ) production are responsible for inherited AD cases. The amyloid cascade hypothesis was proposed to explain the pathogeny. Despite the fact that Aβ is considered as the main culprit of the pathology, most clinical trials focusing on Aβ failed and suggested that earlier interventions are needed to influence the course of AD. Therefore, identifying risk factors that predispose to AD is crucial. Among them, the epsilon 4 allele of the apolipoprotein E gene that encodes the major brain lipid carrier and metabolic disorders such as obesity and type 2 diabetes were identified as AD risk factors, suggesting that abnormal lipid metabolism could influence the progression of the disease. Among lipids, fatty acids (FAs) play a fundamental role in proper brain function, including memory. Peroxisome proliferator-activated receptor α (PPARα) is a master metabolic regulator that regulates the catabolism of FA. Several studies report an essential role of PPARα in neuronal function governing synaptic plasticity and cognition. In this review, we explore the implication of lipid metabolism in AD, with a special focus on PPARα and its potential role in AD therapy.

scholarly journals Galectin-3: a key player in microglia-mediated neuroinflammation and Alzheimer's disease

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yinyin Tan ◽  
Yanqun Zheng ◽  
Daiwen Xu ◽  
Zhanfang Sun ◽  
Huan Yang ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Neurofibrillary Tangles ◽  
Microglial Activation ◽  
Amyloid Β ◽  
Review Article ◽  
Common Cause ◽  
Galectin 3

AbstractAlzheimer’s disease (AD) is the most common cause of dementia and is characterized by the deposition of extracellular aggregates of amyloid-β (Aβ), the formation of intraneuronal tau neurofibrillary tangles and microglial activation-mediated neuroinflammation. One of the key molecules involved in microglial activation is galectin-3 (Gal-3). In recent years, extensive studies have dissected the mechanisms by which Gal-3 modulates microglial activation, impacting Aβ deposition, in both animal models and human studies. In this review article, we focus on the emerging role of Gal-3 in biology and pathobiology, including its origin, its functions in regulating microglial activation and neuroinflammation, and its emergence as a biomarker in AD and other neurodegenerative diseases. These aspects are important to elucidate the involvement of Gal-3 in AD pathogenesis and may provide novel insights into the use of Gal-3 for AD diagnosis and therapy.

scholarly journals Current Progress on Peroxisome Proliferator-activated Receptor Gamma Agonist as an Emerging Therapeutic Approach for the Treatment of Alzheimer's Disease: An Update

2019 ◽  
Vol 17 (3) ◽  
pp. 232-246 ◽  
Author(s):  
Mahmood Ahmad Khan ◽  
Qamre Alam ◽  
Absarul Haque ◽  
Mohammad Ashafaq ◽  
Mohd Jahir Khan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Therapeutic Target ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Synaptic Function ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pparγ Agonist

Alzheimer’s disease (AD) is an age-related progressive neurodegenerative disorder, characterized by the deposition of amyloid-β within the brain parenchyma resulting in a significant decline in cognitive functions. The pathophysiological conditions of the disease are recognized by the perturbation of synaptic function, energy and lipid metabolism. In Addition deposition of amyloid plaques also triggers inflammation upon the induction of microglia. Peroxisome proliferatoractivated receptors (PPARs) are ligand-activated transcription factors known to play important role in the regulation of glucose absorption, homeostasis of lipid metabolism and are further known to involved in repressing the expression of genes related to inflammation. Therefore, agonists of this receptor represent an attractive therapeutic target for AD. Recently, both clinical and preclinical studies showed that use of Peroxisome proliferator-activated receptor gamma (PPARγ) agonist improves both learning and memory along with other AD related pathology. Thus, PPARγ signifies a significant new therapeutic target in treating AD. In this review, we have shed some light on the recent progress of how, PPARγ agonist selectively modulated different cellular targets in AD and its amazing potential in the treatment of AD.

scholarly journals Is There Any Evidence of Monocytes Involvement in Alzheimer’s Disease? A Pilot Study on Human Postmortem Brain

2021 ◽  
pp. 1-11
Author(s):  
Camelia-Maria Monoranu ◽  
Tim Hartmann ◽  
Sabrina Strobel ◽  
Helmut Heinsen ◽  
Peter Riederer ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Human Brain ◽  
Amyloid Β ◽  
Occipital Lobe ◽  
Inflammatory Cells ◽  
Brain Regions ◽  
Postmortem Brain

Background: The role of neuroinflammation has become more evident in the pathogenesis of neurodegenerative diseases. Increased expression of microglial markers is widely reported in Alzheimer’s disease (AD), but much less is known about the role of monocytes in AD pathogenesis. In AD animal models, bone marrow-derived monocytes appear to infiltrate the parenchyma and contribute to the phagocytosis of amyloid-β depositions, but this infiltration has not been established in systematic studies of the human brain postmortem. Objective: In addition to assessing the distribution of different subtypes of microglia by immunostaining for CD68, HLA-DR, CD163, and CD206, we focused on the involvement of C-chemokine receptor type2 (CCR2) positive monocytes during the AD course. Methods: We used formalin-fixed and paraffin-embedded tissue from four vulnerable brain regions (hippocampus, occipital lobe, brainstem, and cerebellum) from neuropathologically characterized AD cases at different Braak stages and age-matched controls. Results: Only singular migrated CCR2-positive cells were found in all brain regions and stages. The brainstem showed the highest number of positive cells overall, followed by the hippocampus. This mechanism of recruitment seems to work less efficiently in the human brain at an advanced age, and the ingress of monocytes obviously takes place in much reduced numbers or not at all. Conclusion: In contrast to studies on animal models, we observed only a quite low level of myeloid monocytes associated with AD pathology. Furthermore, we provide evidence associating early microglial reactions carried out in particular by pro-inflammatory cells with early effects on tangle- and plaque-positive vulnerable brain regions.

scholarly journals Alzheimer's Disease: Another Target for Heparin Therapy

2009 ◽  
Vol 9 ◽  
pp. 891-908 ◽  
Author(s):  
Luigi Bergamaschini ◽  
Emanuela Rossi ◽  
Carlo Vergani ◽  
Maria Grazia De Simoni
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Β ◽  
The Elderly ◽  
Heparin Therapy ◽  
Therapeutic Interventions ◽  
Neuronal Viability ◽  
Β Protein ◽  
Tissue Changes

Alzheimer's disease (AD) is the leading cause of dementia and cognitive decline in the elderly. Brain tissue changes indicate that the two main proteins involved in AD are amyloid-β(A-β), which is associated with the formation of senile amyloid plaques, and tau, which is associated with the formation of neurofibrillary tangles. Although a central role for A-β in the pathogenesis of AD is indisputable, considerable evidence indicates that A-β production is not the sole culprit in AD pathology. AD is also accompanied by an inflammatory response that contributes to irreversible changes in neuronal viability and brain function, and accumulating evidence supports the pivotal role of complement and contact systems in its pathogenesis and progression. The complexity of AD pathology provides numerous potential targets for therapeutic interventions. Compounds that interact directly with A-β protein or interfere with its production and/or aggregation can reduce the inflammatory and neurotoxic effects of A-β, and heparin, a glycosaminoglycan mixture currently used in the prophylaxis and treatment of thrombosis, might be a candidate, as recent research has been extended to consider its nonanticoagulant properties, including its modulation of various proteases and anti-inflammatory activity.

scholarly journals Cholesterol and ApoE in Alzheimer’s disease

OCL ◽  
2018 ◽  
Vol 25 (4) ◽  
pp. D407 ◽  
Author(s):  
Marie-Claude Potier ◽  
Linda Hanbouch ◽  
Catherine Marquer
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Animal Models ◽  
Amyloid Precursor Protein ◽  
Molecular Dynamic ◽  
Amyloid Β ◽  
Aβ Peptides ◽  
Dynamic Studies ◽  
Biochemical Studies

Genetic, neuropathological and biochemical studies suggest strong links between cholesterol, the apolipoprotein E (APOE) and Alzheimer’s disease (AD), both in humans and in animal models of the disease. From the literature and our work, we can predict that transient increase of the levels of cholesterol at the membrane of neurons would profoundly affect the processing of the transmembrane Amyloid Precursor Protein (APP) by triggering its clathrin dependent endocytosis and the resulting production of amyloid-β (Aβ) peptides. Here, we will review these data together with structural and molecular dynamic studies that characterized the role of cholesterol on APP conformation and positioning at the membrane. Specifically decreasing brain cholesterol or replacing it with plant sterols crossing the blood brain barrier appear like promising strategies to either delay or counteract the development of sporadic AD.

scholarly journals The Role of Galanin, Alarin, Irisin, PGC1-Α and BDNF in the Pathophysiology of Alzheimer's disease

2021 ◽  
Vol 8 (06) ◽  
pp. 5498-5507
Author(s):  
Huseyin Fatih Gul ◽  
Caner Yildirim ◽  
Can Emre Erdogan ◽  
Ozlem Gul ◽  
Nazlı Koc
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Control Group ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
Cross Sectional ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Mean ◽  
Positive Correlations

The roles of novel peptides such as peroxisome proliferator-activated receptor gamma coactivator 1- alpha (PGC1-α), irisin, brain-derived neurotrophic factor (BDNF), galanin and alarin in Alzheimer's disease (AD) are not fully known. It was aimed to plasma levels of the novel peptides that may affect the pathophysiology of AD were examined. This study was conducted as a cross-sectional. The study consisted of two groups, including 45 newly diagnosed individuals with AD and 45 healthy individuals. The peptide levels in plasma samples collected from the groups were measured by the ELISA method. The mean plasma peptide levels and age differences, between the groups, and the correlations between them were analyzed by the statistically. The means ages of both groups were over 65 years old. When plasma PGC1-α, irisin, BDNF, galanin, and alarin levels between the groups were examined, decreases were found in the group with AD (3.56±0.79ng/mL, 16.33±4.07ng/mL, 3.36±1.47ng/mL, 13.93±4.24ng/L, 31.99±11.89pg/mL, respectively) compared to the control group (4.23±1.31ng/mL, 22.19±9.61ng/mL, 4.58±2.10ng/mL, 14.4±9.01ng/L, 54.93±15.80pg/mL, respectively). In the negative correlations observed between age and plasma peptide levels. Significant positive correlations were observed between plasma PGC1-α levels and irisin, alarin, and BDNF, and the significant positive correlations were also observed between plasma BDNF levels and irisin and alarin. As far as we know, the study is the first report in which the peptides mentioned in AD were examined together. We consider that more detailed studies are needed to shed light on the roles and mechanisms of these peptides in AD.

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