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Role of Vitamin D and Antioxidant Functional Foods in the Prevention and Treatment of Alzheimer’s Disease Pathology
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
There several hypotheses regarding AD genesis. In the amyloid hypothesis, there are imbalances in the production of APP versus clearance of amyloid β that can be resistant to degradation. These are affected by β- and ƴ-secretase enzymes (Lane et al., 2018). Extracellular splitting of APP in the shorter soluble portion is mediated by BACE 1 (β- site—APP—cleaving enzyme). Moreover, the proteolytic degradation of β amyloid is mediated by neprilysin (NEP) and the insulin-degrading enzyme. The activity of this enzyme in areas affected by AD, such as the hippocampus, can be impaired leading to disease progression. The endosomal lysosomal pathway is also important to process APP, and the dysfunction of these processes have been associated with disease establishment and progression (Sanabria-Castro, Alvarado-Echeverria, & Monge-Bonilla, 2017).
Commonly prescribed drugs
Published in Alistair Burns, Michael A Horan, John E Clague, Gillian McLean, Geriatric Medicine for Old-Age Psychiatrists, 2005
Alistair Burns, Michael A Horan, John E Clague, Gillian McLean
Other antidiabetic agents include acarbose, an inhibitor of intestinal a- glucosidases, which delays the digesti�n and absorption of starch; nateglin- ide and repaglinide, which stimulate insulin release; and pioglitazone and rosiglitazone, which reduce peripheral insulin resistance.
Cognitive Dysfunction and Depression in Older Adults with Diabetes
Published in Medha N. Munshi, Lewis A. Lipsitz, Geriatric Diabetes, 2007
However, cerebral and cognitive effects of insulin have been greatly challenged in the context of aging, chronic hyperinsulinemia, and insulin resistance. Elderly diabetes patients, most of them type 2, are known to have abnormal insulin metabolism, specifically insulin resistance and chronic, compensatory hyperinsulinemia. Abnormally high insulin levels have been associated for decades with heart disease and obesity. Recent lines of research have even cast excess insulin in a dark light. Over the past few years, the role of hyperinsulinemia in implicating the metabolism of Aβ as well as the development of cognitive dysfunction and dementia has been enthusiastically explored. Senile plaque, the hallmark of AD, contains an extracellular aggregation of heterogeneous Aβ peptides derived from amyloid precursor protein (APP). APP undergoes proteolytic β-secretase and γ-secretase activities to generate Aβ40 and Aβ42 peptides, the predominant Aβ variants. An important hypothesis of AD, the amyloid hypothesis, states that Aβ initiates a process resulting in AD (45). Aβ is cleared through microglia low-density lipoprotein cholesterol (LDL)-receptor–mediated uptake or through proteolytic degradation. The proteolytic degradation of Aβ involves insulin-degrading enzyme (IDE). In addition to the degrading of Alzheimer’s protein (Aβ), IDE also degrades insulin and in fact demonstrates a strong preference for insulin over Aβ. Gasparini et al. by incubating neurons in vitro with insulin, suggested that insulin increased extracellular Aβ both by reducing IDE-mediated Aβ degradation and by stimulating Aβ secretion (46). An animal study by Farris et al. demonstrated that transgenic mouse with IDE gene entirely knocked out developed typical features of AD and type 2 DM, namely hyperinsulinemia, glucose intolerance, and increased brain levels of Aβ (47). The next level of evidence of insulin and amyloid metabolism has moved from cell cultures and animal models to human study. By experimentally raised plasma insulin to levels commonly encountered in many patients with type 2 DM, Watson et al. found that insulin infusion led to an increase in cerebrospinal fluid Aβ levels, most notably in older subjects (48).
The aquaporin-4 water channel and updates on its potential as a drug target for Alzheimer’s disease
Published in Expert Opinion on Therapeutic Targets, 2023
Bret Silverglate, Xiaoyi Gao, Hannah P. Lee, Peter Maliha, George T. Grossberg
The imbalance between Aβ clearance and production is believed to be one of the main pathogenic mechanisms in AD. Aβ is a 4kDa peptide derived from the larger amyloid precursor protein, and it was first isolated as the principal component of amyloid deposits in the brain and cerebrovasculature of AD and Down’s Syndrome patients [43]. Soluble Aβ aggregates into insoluble Aβ plaques, resulting in Aβ deposition. Aβ plaques disturb synaptic function, which plays a major role in AD [44]. Two major enzymes, neprilysin (NEP) and insulin degrading enzyme (also known as insulysin; IDE), are believed to be responsible for most Aβ degradation [45]. Cathepsin, which plays a role in lysosomal degradation, also helps degrade Aβ [46]. Despite substantial catabolism within the brain, a significant amount of Aβ remains undegraded, requiring mechanisms to transport Aβ across the blood-brain barrier (BBB) [47]. One recently proposed pathway for parenchymal protein clearance, the glymphatic system, is based on AQP4-dependent trans-astrocytic flow [48], bringing attention to a close relationship between AQP4 and AD.
Familial diabetes predisposes PCOS patients to insulin resistance (IR), reproductive impairment and hepatic dysfunction: effects of d-chiro inositol (DCI) and alpha lipoic acid (ALA) administration on hepatic insulin extraction (HIE) index
Published in Gynecological Endocrinology, 2022
Alessandro D. Genazzani, Christian Battipaglia, Tabatha Petrillo, Nicola Piacquadio, Fedora Ambrosetti, Melania Arnesano, Elisa Semprini, Alessandra Sponzilli, Veronica Tomatis, Tommaso Simoncini
HIE index computation discloses that HIE decreases significantly after the treatment interval in our PCOS patients. Such decrease is easily explained by the fact that insulin clearance by liver function is improved thus showing a significant decrease in HIE. When patients were considered according to the presence or absence of familiar diabetes, the former PCOS patients showed that in baseline conditions the HIE profile, after the fast rise within 30 min from the glucose load, remained stable and high, with no change and no decay within 2 h from the glucose load. Conversely, in PCOS patients without familiar diabetes the HIE index promptly decreased significantly after 30 min from the glucose load both before and after the treatment interval. This observation is of great interest since supports the hypothesis that while PCOS without familiar diabetes have no defects in liver ability to clear insulin, independently from having or not the integrative treatment, PCOS with familiar diabetes recovered such ability after the integrative treatment, as demonstrated by the significant decrease of the HIE within 60 min after the glucose load. In other words, it is plausible saying that in this kind of PCOS population a certain degree of the IR and the compensatory hyperinsulinemia is not due only to greater pancreatic production but also to a reduced clearance of insulin. Such observations are in line and confirm what previously demonstrated by Leissring et al. [32] in regards to Insulin Degrading Enzyme (IDE), expressed by liver hepatocytes, whose IDE function/expression is reduced by diabetes and/or obesity [32, 40].
The relationship between cholesterol level and Alzheimer’s disease-associated APP proteolysis/Aβ metabolism
Published in Nutritional Neuroscience, 2019
Chaoqun Wang, Yikai Shou, Jie Pan, Yue Du, Cuiqing Liu, Huanhuan Wang
The major Aβ degrading enzymes are insulin-degrading enzyme (IDE) and neprilysin (NEP).131,132 IDE is a kind of zinc metallo-endopeptidase that hydrolyses several regulatory peptides and exists in the cytoplasm, peroxisome, vesicles, and on the cell surface.133 Multiple lines of evidence, including IDE knockout mice134 and IDE overexpressing transgenic mice,135 support the role for IDE in Aβ degradation. Evidence has shown that a high-cholesterol diet could result in a reduction in IDE expression in the mouse hippocampus and cortex, leading to a decrease in Aβ degradation.104,123 In LDL receptor deficiency-induced hypercholesterolemic mice, a significant reduction in IDE expression and Aβ accumulation were found.136,137 However, another study claimed that hyperlipidaemia induced by a high-cholesterol diet elevated the IDE level,75 and the function and activity of IDE could be influenced by membrane cholesterol,138 contrary to the results of previous studies. A possible explanation for this discrepancy may be that, upon initial elevation of the cholesterol level, Aβ generation and IDE expression increase, facilitating the degradation of Aβ; however, under a long-term high cholesterol level, IDE activity is suppressed, leading to a decrease in Aβ degradation. In addition, an acute high cholesterol level may primarily participate in the variation of membrane cholesterol and LR composition, which could enhance IDE activity.