Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Chakrabarti, Sasanka; Khemka, Vineet Kumar; Banerjee, Anindita; Chatterjee, Gargi; Ganguly, Anirban; Biswas, Atanu

doi:10.14336/ad.2014.002

Cited by 107 publications

(79 citation statements)

References 187 publications

(242 reference statements)

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“…Although there are some genetic risk factors for AD, most cases are sporadic with the underlying etiology of the disease unknown [78]. However evidence suggests that diet and lifestyle markedly influence the risk of developing AD [79].…”

Section: A Link Between Leptin and Alzheimer's Disease (Ad)mentioning

confidence: 99%

Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

McGregor

Harvey

2017

Neurochem Res

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Discovery of the obese (ob) gene in 1994 via positional cloning techniques enabled insight into the physiological system that controls body weight and energy expenditure [1]. Subsequent investigations identified the ob gene product as a 16 kDa protein that reduced food intake and increased energy expenditure in genetically obese (ob/ob) rodent models, indicating a pivotal role in regulating energy homeostasis. This protein was termed leptin [2,3].Leptin is primarily produced and secreted by white adipose tissue and circulates in proportion to adipose mass [3]. The leptin receptor (Ob-R) is encoded by the diabetes (db) gene [4]. Leptin gains access to the hypothalamus to regulate energy homeostasis via a saturable transport mechanism or by binding to receptors at the blood-brain barrier interface [5]. However recent evidence suggests that leptin can also be made locally within the CNS as leptin mRNA and protein has been detected within the brain [6].At least six different isoforms (Ob-R a-f ) of Ob-R exist (Fig. 1) as a result of alternative splicing of the db gene [7,8]. Each isoform has an identical N-terminal ligand-binding domain but a differential C-terminal region required for signalling. Each isoform gives rise to a single membranespanning receptor with the exception of Ob-R e which is thought to circulate as a soluble leptin binding protein. The remaining Ob-R isoforms have either a short intracellular domain containing 30-40 cytoplasmic residues (Ob-R a,c,d,f ) or a large intracellular domain consisting of 302 residues (known as the long form of the receptor (Ob-R b ), which is the most signalling competent form of the receptor [9].Abstract Growing evidence indicates that the endocrine hormone leptin regulates hippocampal synaptic function in addition to its established role as a hypothalamic satiety signal. Indeed, numerous studies show that leptin facilitates the cellular events that underlie hippocampal learning and memory including activity-dependent synaptic plasticity and glutamate receptor trafficking, indicating that leptin may be a potential cognitive enhancer. Although there has been extensive investigation into the modulatory role of leptin at hippocampal Schaffer collateral (SC)-CA1 synapses, recent evidence indicates that leptin also potently regulates excitatory synaptic transmission at the anatomically distinct temporoammonic (TA) input to hippocampal CA1 neurons. The cellular mechanisms underlying activity-dependent synaptic plasticity at TA-CA1 synapses differ from those at SC-CA1 synapses and the TA input is implicated in spatial and episodic memory formation. Furthermore, the TA input is an early target for neurodegeneration in Alzheimer's disease (AD) and aberrant leptin function is linked to AD. Here, we review the evidence that leptin regulates hippocampal synaptic function at both SC-and TA-CA1 synapses and discuss the consequences for neurodegenerative disorders like AD.

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Section: A Link Between Leptin and Alzheimer's Disease (Ad)mentioning

confidence: 99%

Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

McGregor

Harvey

2017

Neurochem Res

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Section: Sporadic Ad With No Known Genetic Mutationsmentioning

confidence: 99%

“…However, other proteins are also known to accumulate, including SNCA, TDP-43 and ACTIN which form Lewy-like bodies and Hirano bodies [42]. In sporadic AD, the symptoms occur later than in the familial forms [42]. However, the complexity and heterogeneity of both symptoms and pathology are widespread in sporadic AD, which may be due to multiple unknown risk factors, mutations in varying genes which have not yet described, but potentially also the diverse effects of environmental factors and potential interaction with genes [42].…”

Section: Sporadic Ad With No Known Genetic Mutationsmentioning

confidence: 99%

“…In sporadic AD, the symptoms occur later than in the familial forms [42]. However, the complexity and heterogeneity of both symptoms and pathology are widespread in sporadic AD, which may be due to multiple unknown risk factors, mutations in varying genes which have not yet described, but potentially also the diverse effects of environmental factors and potential interaction with genes [42]. To date, three studies have been performed to modulate sporadic AD using patient-specific iPSCs.…”

Section: Sporadic Ad With No Known Genetic Mutationsmentioning

confidence: 99%

“…The polymorphism of the APOE gene is a risk factor for the disease and presence of the ε4 allelle (APOE4) has been linked with AD [42]. One copy of this allele increases the risk of AD twofold, whereas two copies increases the risk of AD by 12-fold [46].…”

Section: Sporadic Cases With Mutations In Apoementioning

confidence: 99%

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Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

Hall¹

2016

Pluripotent Stem Cells - From the Bench to the Clinic

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Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer's disease, frontotemporal dementia and Parkinson's disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only some of the phenotype can be observed in-vitro, but these phenotypes, when compared to the patient, correlate extremely well. Many studies have found novel molecular mechanisms involved in the disease and therefore elucidate new potential targets for reversing the phenotype. Future research that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about these diseases, but will lead to even more findings in the future as gene and cell culture technology continues to develop.

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CSF amino acid profiles in ICV‐streptozotocin‐induced sporadic Alzheimer's disease in male Wistar rat: a metabolomics and systems biology perspective

Barzegar Behrooz,

Latifi‐Navid,

Lotfi

et al. 2024

FEBS Open Bio

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Alzheimer's disease (AD) is an increasingly important public health concern due to the increasing proportion of older individuals within the general population. The impairment of processes responsible for adequate brain energy supply primarily determines the early features of the aging process. Restricting brain energy supply results in brain hypometabolism prior to clinical symptoms and is anatomically and functionally associated with cognitive impairment. The present study investigated changes in metabolic profiles induced by intracerebroventricular‐streptozotocin (ICV‐STZ) in an AD‐like animal model. To this end, male Wistar rats received a single injection of STZ (3 mg·kg−1) by ICV (2.5 μL into each ventricle for 5 min on each side). In the second week after receiving ICV‐STZ, rats were tested for cognitive performance using the Morris Water Maze test and subsequently prepared for positron emission tomography (PET) to confirm AD‐like symptoms. Tandem Mass Spectrometry (MS/MS) analysis was used to detect amino acid changes in cerebrospinal fluid (CFS) samples. Our metabolomics study revealed a reduction in the concentrations of various amino acids (alanine, arginine, aspartic acid, glutamic acid, glycine, isoleucine, methionine, phenylalanine, proline, serine, threonine, tryptophane, tyrosine, and valine) in CSF of ICV‐STZ‐treated animals as compared to controls rats. The results of the current study indicate amino acid levels could potentially be considered targets of nutritional and/or pharmacological interventions to interfere with AD progression.

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Metabolic Risk Factors of Sporadic Alzheimer's Disease: Implications in the Pathology, Pathogenesis and Treatment

Cited by 107 publications

References 187 publications

Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

Leptin Regulation of Synaptic Function at Hippocampal TA-CA1 and SC-CA1 Synapses: Implications for Health and Disease

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

CSF amino acid profiles in ICV‐streptozotocin‐induced sporadic Alzheimer's disease in male Wistar rat: a metabolomics and systems biology perspective

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