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 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 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 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 Somatostatin and Astroglial Involvement in the Human Limbic System in Alzheimer’s Disease

2021 ◽  
Vol 22 (16) ◽  
pp. 8434
Author(s):  
Melania Gonzalez-Rodriguez ◽  
Veronica Astillero-Lopez ◽  
Patricia Villanueva-Anguita ◽  
M. Eugenia Paya-Rodriguez ◽  
Alicia Flores-Cuadrado ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Distribution ◽  
Olfactory Bulb ◽  
Limbic System ◽  
Tau Protein ◽  
Amyloid Β ◽  
The Elderly ◽  
Amyloid Β Peptide ◽  
Human Hippocampus

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-β peptide (Aβ) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer’s disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aβ and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aβ peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer’s disease pathogenesis.

scholarly journals Lipid Metabolism and Neuroinflammation in Alzheimer's Disease: A Role for Liver X Receptors

2012 ◽  
Vol 33 (5) ◽  
pp. 715-746 ◽  
Author(s):  
Jihong Kang ◽  
Serge Rivest
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Metabolism ◽  
Neurodegenerative Disease ◽  
Cholesterol Metabolism ◽  
Significant Risk ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Liver X Receptors ◽  
X Receptors

Liver X receptors (LXR) are nuclear receptors that have emerged as key regulators of lipid metabolism. In addition to their functions as cholesterol sensors, LXR have also been found to regulate inflammatory responses in macrophages. Alzheimer's disease (AD) is a neurodegenerative disease characterized by a progressive cognitive decline associated with inflammation. Evidence indicates that the initiation and progression of AD is linked to aberrant cholesterol metabolism and inflammation. Activation of LXR can regulate neuroinflammation and decrease amyloid-β peptide accumulation. Here, we highlight the role of LXR in orchestrating lipid homeostasis and neuroinflammation in the brain. In addition, diabetes mellitus is also briefly discussed as a significant risk factor for AD because of the appearing beneficial effects of LXR on glucose homeostasis. The ability of LXR to attenuate AD pathology makes them potential therapeutic targets for this neurodegenerative disease.

scholarly journals The Conspicuous Link between Ear, Brain and Heart–Could Neurotrophin-Treatment of Age-Related Hearing Loss Help Prevent Alzheimer’s Disease and Associated Amyloid Cardiomyopathy?

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 900
Author(s):  
Sergey Shityakov ◽  
Kentaro Hayashi ◽  
Stefan Störk ◽  
Verena Scheper ◽  
Thomas Lenarz ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Decline ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
The Elderly ◽  
Amyloid Β Peptide ◽  
Age Related ◽  
Amyloid Cardiomyopathy ◽  
Age Related Hearing Loss

Alzheimer’s disease (AD), the most common cause of dementia in the elderly, is a neurodegenerative disorder associated with neurovascular dysfunction and cognitive decline. While the deposition of amyloid β peptide (Aβ) and the formation of neurofibrillary tangles (NFTs) are the pathological hallmarks of AD-affected brains, the majority of cases exhibits a combination of comorbidities that ultimately lead to multi-organ failure. Of particular interest, it can be demonstrated that Aβ pathology is present in the hearts of patients with AD, while the formation of NFT in the auditory system can be detected much earlier than the onset of symptoms. Progressive hearing impairment may beget social isolation and accelerate cognitive decline and increase the risk of developing dementia. The current review discusses the concept of a brain–ear–heart axis by which Aβ and NFT inhibition could be achieved through targeted supplementation of neurotrophic factors to the cochlea and the brain. Such amyloid inhibition might also indirectly affect amyloid accumulation in the heart, thus reducing the risk of developing AD-associated amyloid cardiomyopathy and cardiovascular disease.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Is it All Said for NSAIDs in Alzheimer’s Disease? Role of Mitochondrial Calcium Uptake

2018 ◽  
Vol 15 (6) ◽  
pp. 504-510 ◽  
Author(s):  
Sara Sanz-Blasco ◽  
Maria Calvo-Rodríguez ◽  
Erica Caballero ◽  
Monica Garcia-Durillo ◽  
Lucia Nunez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Amyloid Β ◽  
Epidemiological Data ◽  
Amyloid Β Peptide ◽  
Aβ Oligomers ◽  
Mitochondrial Potential ◽  
Disease Modifying Drugs ◽  
Definitive Evidence

Objectives: Epidemiological data suggest that non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Unfortunately, recent trials have failed in providing compelling evidence of neuroprotection. Discussion as to why NSAIDs effectivity is uncertain is ongoing. Possible explanations include the view that NSAIDs and other possible disease-modifying drugs should be provided before the patients develop symptoms of AD or cognitive decline. In addition, NSAID targets for neuroprotection are unclear. Both COX-dependent and independent mechanisms have been proposed, including γ-secretase that cleaves the amyloid precursor protein (APP) and yields amyloid β peptide (Aβ). Methods: We have proposed a neuroprotection mechanism for NSAIDs based on inhibition of mitochondrial Ca2+ overload. Aβ oligomers promote Ca2+ influx and mitochondrial Ca2+ overload leading to neuron cell death. Several non-specific NSAIDs including ibuprofen, sulindac, indomethacin and Rflurbiprofen depolarize mitochondria in the low µM range and prevent mitochondrial Ca2+ overload induced by Aβ oligomers and/or N-methyl-D-aspartate (NMDA). However, at larger concentrations, NSAIDs may collapse mitochondrial potential (ΔΨ) leading to cell death. Results: Accordingly, this mechanism may explain neuroprotection at low concentrations and damage at larger doses, thus providing clues on the failure of promising trials. Perhaps lower NSAID concentrations and/or alternative compounds with larger dynamic ranges should be considered for future trials to provide definitive evidence of neuroprotection against AD.

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