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Pathophysiological links bridging type 2 diabetes and Alzheimer's disease: the puzzle pieces put together. IDE, insulin degrading enzyme; NADP + , oxidized form of nicotinamide adenine dinucleotide phosphate; NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; AGEs, advanced glycation endproducts; RAGEs, receptors for advanced glycation end-products; LOX, lipoxygenase; PLA2, phospholipase A2; ROS, reactive oxygen species; NO, nitric oxide; cGMP, cyclic guanosine monophosphate; cAMP, cyclic adenosine monophosphate; PDE, phosphodiesterase; GLP-1, glucagon-like peptide 1; T2D, type 2 diabetes; GSK-3β, glycogen synthase kinase 3β; GLUT-1, glucose transporter 1; BACE-1, beta-secretase; BBB, blood-brain barrier; CNS, central nervous system; Aβ, amyloid β; IAPP, islet amyloid polypeptide; AChE, acetylcholinesterase; APOE-ε4, apolipoprotein E-ε4.
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Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two age-related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidenc...
Citations
... This in turn leads to uncontrollable levels of glucose or sugars in blood circulation and affects energy metabolism and kidney function in the affected individual. 6 Types of diabetes Type 1 diabetes mellitus (T1D) is an autoimmune disease that leads to the destruction of insulin-producing pancreatic beta cells. 7 Type 2 Diabetes Mellitus (T2DM) is one of the most common metabolic illness worldwide and its development is primarily caused by a combination of two main factors: faulty insulin release by pancreatic β-cells and the incapability of insulin-sensitive tissues to respond to insulin 8 ...
This book series invites all the Specialists, Professors, Doctors, Scientists, Academicians, Healthcare professionals, Nurses, Students, Researchers, Business Delegates, and Industrialists across the globe to publish their insights and convey recent developments in the field of Nursing, Pharmaceutical Research and Innovations in Pharma Industry. Book series on Pharmacy and Nursing covers research work in a set of clinical sciences and medicine.
... Other bi-specific targets are β-Amyloid and human islet amyloid polypeptide (hIAPP), which is implicated in type 2 diabetes (T2D). Increasing evidence suggests that AD and T2D may be correlated with each other [54]. ...
... Other bi-specific targets are β-Amyloid and human islet amyloid polypeptide (hIAPP), which is implicated in type 2 diabetes (T2D). Increasing evidence suggests that AD and T2D may be correlated with each other [54]. The structure of the N-terminal region of the AL fibril could take difference conformations. ...
Citation: Bai, J.; Li, X.; Zhao, J.; Zong, H.; Yuan, Y.; Wang, L.; Zhang, X.; Ke, Y.; Han, L.; Xu, J.; et al. Re-Engineering Therapeutic Anti-Aβ Monoclonal Antibody to Target Amyloid Light Chain. Int. J. Mol. Sci. 2024, 25, 1593. https://doi. Abstract: Amyloidosis involves the deposition of misfolded proteins. Even though it is caused by different pathogenic mechanisms, in aggregate, it shares similar features. Here, we tested and confirmed a hypothesis that an amyloid antibody can be engineered by a few mutations to target a different species. Amyloid light chain (AL) and β-amyloid peptide (Aβ) are two therapeutic targets that are implicated in amyloid light chain amyloidosis and Alzheimer's disease, respectively. Though crenezumab, an anti-Aβ antibody, is currently unsuccessful, we chose it as a model to computationally design and prepare crenezumab variants, aiming to discover a novel antibody with high affinity to AL fibrils and to establish a technology platform for repurposing amyloid monoclonal antibodies. We successfully re-engineered crenezumab to bind both Aβ42 oligomers and AL fibrils with high binding affinities. It is capable of reversing Aβ42-oligomers-induced cytotoxicity, decreasing the formation of AL fibrils, and alleviating AL-fibrils-induced cytotoxicity in vitro. Our research demonstrated that an amyloid antibody could be engineered by a few mutations to bind new amyloid sequences, providing an efficient way to reposition a therapeutic antibody to target different amyloid diseases.
... Higher concentrations of HNE may interfere with sodium-calcium pumps or glucose/glutamate transporters, resulting in disruption of neuronal gradients and ultimately cell death. According to studies, 4-HNE overproduction also increases β-and γ-secretase (enzymes responsible for pathologic amyloid protein processing), thereby inducing Aβ production in the brain (de Matos et al., 2018). Higher levels of 4-HNE in the cerebrospinal fluid, plasma, urine, and brains of AD patients suggest that HNE could be a potential biomarker for the early diagnosis of AD (Kimura, 2016). ...
Learning and memory storage are the fundamental activities of the brain. Aberrant expression of synaptic molecular markers has been linked to memory impairment in AD. Aging is one of the risk factors linked to gradual memory loss. It is estimated that approximately 13 million people worldwide will have AD by 2050. A massive amount of oxidative stress is kept under control by a complex network of antioxidants, which occasionally fails and results in neuronal oxidative stress. Increasing evidence suggests that ROS may affect many pathological aspects of AD, including Aβ accumulation, tau hyperphosphorylation, synaptic plasticity, and mitochondrial dysfunction, which may collectively result in neurodegeneration in the brain. Further investigation into the relationship between oxidative stress and AD may provide an avenue for effective preservation and pharmacological treatment of this neurodegenerative disease. In this review, we briefly summarize the cellular mechanism underlying Aβ induced synaptic dysfunction. Since oxidative stress is common in the elderly and may contribute to the pathogenesis of AD, we also shed light on the role of antioxidant and inflammatory pathways in oxidative stress adaptation, which has a potential therapeutic target in neurodegenerative diseases.
... Another well-known fact is that AChE expression and activity control the dynamic concentration of ACh in the cholinergic synapses of the brain (Buckingham et al. 2009). The altered levels of AChE in AD patient's brains and plasma, as well as the co-localization of this enzyme with Aβ deposits in the hippocampus, suggest that this enzyme may have a crucial role in the pathogenesis of AD (Mushtaq et al. 2014;de Matos et al. 2018). In the present study, AChE activity was remarkably increased in the hippocampal homogenates of SCO/HMM-treated rats, compared to their normal surrogates. ...
Alzheimer’s disease (AD) is one of the most prevalent neurodegenerative illnesses, and yet, no workable treatments have been discovered to prevent or reverse AD. Curcumin (CUR), the major polyphenolic compound of turmeric (Curcuma longa) rhizomes, and Ginkgo biloba extract (GBE) are natural substances derived from conventional Chinese herbs that have long been shown to provide therapeutic advantages for AD. The uptake of curcumin into the brain is severely restricted by its low ability to cross the blood–brain barrier (BBB). Meanwhile, GBE has been shown to improve BBB permeability. The present study evaluated the neuroprotective effects and pharmacokinetic profile of curcumin and GBE combination to find out whether GBE can enhance curcumin’s beneficial effects in AD by raising its brain concentration. Results revealed that CUR + GBE achieved significantly higher levels of curcumin in the brain and plasma after 30 min and 1 h of oral administration, compared to curcumin alone, and this was confirmed by reversed phase high-performance liquid chromatography (RP-HPLC). The effect of combined oral treatment, for 28 successive days, on cognitive function and other AD-like alterations was studied in scopolamine-heavy metal mixtures (SCO + HMM) AD model in rats. The combination reversed at least, partially on the learning and memory impairment induced by SCO + HMM. This was associated with a more pronounced inhibitory effect on acetylcholinesterase (AChE), caspase-3, hippocampal amyloid beta (Aβ1-42), and phosphorylated tau protein (p-tau) count, and pro-inflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukine-1beta (IL-1β), as compared to the curcumin alone-treated group. Additionally, the combined treatment significantly decreased lipid peroxidation (MDA) and increased levels of reduced glutathione (GSH), when compared with the curcumin alone. These findings support the concept that the combination strategy might be an alternative therapy in the management/prevention of neurological disorders. This study sheds light on a new approach for exploring new phyto-therapies for AD and emphasizes that more research should focus on the synergic effects of herbal drugs in future.
Graphical abstract
... If the trend evolves as predicted, the number of adults with diabetes will have risen to an astonishing 783 million by 2045 [1]. However, it is estimated that over 90% of the diabetes population has type 2 diabetes-a rather preventable and, at times, even reversible type of diabetes that mostly arises from unhealthy lifestyle choices, including the consumption of foods with a high fat content and lack of physical activity [1,2]. Dietary changes towards an increased intake of nutritious and bioactive-rich plant-based foods, such as whole grains, nuts, seeds, legumes, fruits, and vegetables, together with reduced consumption of saturated fatty acids, refined sugars, and red meats, have been proven to work effectively in the prevention and management of type 2 diabetes [3,4]. ...
The type 2 diabetes epidemic is real and hardly coming to an end in the upcoming years. The efforts of the scientific community to develop safer and more effective compounds for type 2 diabetes based on the structure of natural (poly)phenols are remarkable and have indeed proven worthwhile after the introduction of gliflozins in clinical practice. However, low-quality reports on the antidiabetic potential of plant-derived lipophilic (poly)phenols continue to pile up in the literature. Many of these compounds continue to be published as promising functional nutrients and antidiabetic pharmaceutical leads without consideration of their Pan-Assay Interference Compounds (PAINS) profile. This evidence-based opinion article conveys the authors’ perspectives on the natural (poly)phenol artillery as a valuable and reliable source of bioactive compounds for diabetes. Ultimately, in light of the already established membrane-perturbing behavior of lipophilic (poly)phenols, together with the multiple benefits that may come with the introduction of a C-glucosyl moiety in bioactive compounds, we aim to raise awareness of the importance of contemplating the shift to (poly)phenol–carbohydrate combinations in the development of functional nutrients, as well as in the early stages of antidiabetic drug discovery.
... T2DM and AD are both age-related diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to T2DM being considered a tangible risk factor for AD onset, known as DE, compared to the normal subjects [2][3][4]22,23]. The onset and progression of DE are complex and involve many factors; AGEs may be an important mechanism of DE [5,[7][8][9][10]. ...
... In T2DM, insulin resistance leads to increase glucose levels, which causes oxidative stress. Subsequently, elevated glucose promotes the production of AGEs, which further triggers insulin resistance and the generation of reactive oxygen species (ROS) [3,22]. ROS generated by AGEs via mitochondrial activation induces oxidative stress, thereby depleting NADPH, which is a major cofactor of antioxidant enzyme systems [39]. ...
Diabetes mellitus (DM) has been recognized as an increased risk factor for cognitive impairment, known as diabetic encephalopathy (DE). Hyperglycemia and insulin resistance are the main initiators of DE, which is related to the accumulation of advanced glycation end products (AGEs). Potassium 2-(1-hydroxypentyl)-benzoate (PHPB), a derivative of 3-n-butylphthalide (dl-NBP), has emerged various properties including improved mitochondrial function, antioxidant, anti-neuroinflammation, and neuroprotective effects. The present study aimed to investigate the neuroprotective effect of PHPB against AGEs accumulation in type 2 diabetic KK-Ay mice model with DE and further explore the underlying mechanisms. The results showed that PHPB markedly ameliorated the spatial learning ability of KK-Ay mice in the Morris water maze and decreased AD-like pathologic changes (Tau hyperphosphorylation) in the cortex. Furthermore, we found that PHPB treatment significantly reduced AGEs generation via up-regulation of glyoxalase-1 (GLO1) protein and enhancement of methylglyoxal (MG) trapping, while there was no obvious difference in levels of glucose in plasma or brain, contents of total cholesterol (TC), triglycerides (TG), and plasma insulin. Also, PHPB treatment improved the insulin signaling pathway by increasing sirtuin1 (SIRT1) deacetylase activity and attenuated oxidative stress evidenced by elevating glucose-6-phosphate dehydrogenase (G-6-PD) protein expression, promoting the production of reduced glutathione (GSH) and reduced nicotinamide adenine dinucleotide phosphate (NADPH), restoring mitochondrial membrane potential, increasing adenosine triphosphate (ATP) generation, and reducing malondialdehyde (MDA) levels in the brain. Taken together, PHPB exhibited a beneficial effect on DE, which involved modulating the SIRT1/insulin signaling pathway and reducing oxidative stress by inhibiting the generation of AGEs.
... Alzheimer's is a disease that increases in frequency with age and occurs in individuals with various co-morbidities. The relationship between AD and other diseases is of particular interest because the co-morbidities may serve as early risk signs for subsequent AD development, may share a treatable pathway or etiology, and may help to slow disease progression in the AD patients [1,2]. Additionally, there may be a protective effect between AD and various cancers, as well as shared pathways that may reveal novel treatment options [3][4][5][6]. ...
(1) Importance: Alzheimer’s disease (AD) is complex and only partially understood. Analyzing the relationship between other more treatable or preventable diseases and AD may help in the prevention and the eventual development of treatments for AD. Risk estimation in a high-risk population, rather than a population already affected with AD, may reduce some bias in risk estimates. (2) Objective: To examine the rates of various comorbidities and cancers in individuals at high-risk for AD, but without a clinical diagnosis, relative to individuals from the same population with normal AD risk. (3) Design, Setting, and Participants: We conducted a study using data from the Utah Population Database (UPDB). The UPDB contains linked data from the Utah Cancer Registry, Utah death certificates, the Intermountain Health patient population, and the University of Utah Health patient population. Subjects were selected based on the availability of ancestral data, linked health information, and self-reported biometrics. (4) Results: In total, 75,877 participants who were estimated to be at high risk for AD based on family history, but who did not have an active AD diagnosis, were analyzed. A lower incidence of diabetes (RR = 0.95, 95% CI [0.92,0.97], p < 0.001), hypertension (RR = 0.97, 95% CI [0.95,0.99], p < 0.001), and heart disease (RR = 0.95, 95% CI [0.93,0.98], p < 0.001) was found. There was no difference in rates of cerebrovascular disease or other forms of dementia. Of the 15 types of cancer analyzed: breast (RR = 1.23, 95% CI [1.16, 1.30], p < 0.001); colorectal (RR = 1.30, 95% CI [1.21, 1.39], p < 0.001); kidney (RR = 1.49, 95% CI (1.29, 1.72), p < 0.001); lung (RR = 1.25, 95% CI [1.13, 1.37], p < 0.001); non-Hodgkin’s Lymphoma (RR = 1.29, 95% CI [1.15, 1.44], p < 0.001); pancreas (RR = 1.34, 95% CI [1.16, 1.55], p < 0.001); stomach (RR = 1.59, 95% CI [1.36, 1.86], p < 0.001); and bladder (RR = 1.40, 95% CI [1.25, 1.56], p < 0.001), cancers were observed in significant excess among individuals at high-risk for AD after correction for multiple testing. (5) Conclusions and Relevance: Since age is the greatest risk factor for the development of AD, individuals who reach more advanced ages are at increased risk of developing AD. Consistent with this, people with fewer comorbidities earlier in life are more likely to reach an age where AD becomes a larger risk. Our findings show that individuals at high risk for AD have a decreased incidence of various other diseases. This is further supported by our finding that our high-risk group was also found to have an increased incidence of various cancers, which also increase in risk with age. There is the possibility that a more meaningful or etiological relationship exists among these various comorbidities. Further research into the etiological relationship between AD and these comorbidities may elucidate these possible interactions.
... IDE, especially, a chaperones-like protein, is reportedly closely associated with AD and PD [20]. Interestingly, in contrast with its downregulation in the brain of mutant mice, plasma IDE was upregulated in mutant mice ( Figure 5(C)), similar with that in patients with sporadic PD in our study (data not shown). ...
... IDE was down-regulated in the SN and STR of CHCHD2 p.T61I mutant mice and the patient-specific, iPSCs-derived DA neurons. IDE is a regulator of the insulin level, which is reportedly associated with neurodegenerative disease [20], eating behaviour, peripheral metabolism [58], and cognitive function [59]. Epidemiological studies suggest that patients with type 2 diabetes mellitus (T2DM) have a high risk (40%) of developing PD [60]. ...
The p.Thr61Ile (p.T61I) mutation in coiled-coil-helix-coiled-coil-helix domain containing 2 (CHCHD2) was deemed a causative factor in Parkinson's disease (PD). However, the pathomechanism of the CHCHD2 p.T61I mutation in PD remains unclear. Few existing mouse models of CHCHD2-related PD completely reproduce the features of PD, and no transgenic or knock-in (KI) mouse models of CHCHD2 mutations have been reported. In the present study, we generated a novel CHCHD2 p.T61I KI mouse model, which exhibited accelerated mortality, progressive motor deficits, and dopaminergic (DA) neurons loss with age, accompanied by the accumulation and aggregation of α-synuclein and p-α-synuclein in the brains of the mutant mice. The mitochondria of mouse brains and induced pluripotent stem cells (iPSCs)-derived DA neurons carrying the CHCHD2 p.T61I mutation exhibited aberrant morphology and impaired function. Mechanistically, proteomic and RNA sequencing analysis revealed that p.T61I mutation induced mitochondrial dysfunction in aged mice likely through repressed insulin-degrading enzyme (IDE) expression, resulting in the degeneration of the nervous system. Overall, this CHCHD2 p.T61I KI mouse model recapitulated the crucial clinical and neuropathological aspects of patients with PD and provided a novel tool for understanding the pathogenic mechanism and therapeutic interventions of CHCHD2-related PD.
... Alzheimer's disease (AD) is the most prominent neurocognitive disorder and the most common cause of dementia in older populations (60-80% of dementia cases) [3]. While the primary causes of early late onset AD (LOAD) is unknown, it has been proposed to be due to accumulation of misfolded beta amyloid peptides (Aβ) into plaques or toxic soluble oligomers, leading to hyperphosphorylation of tau and neurofibrillary tangles deposition in the brain [4]. ...
... The main neurodegenerative disorders that underlie most cases of MCI and dementia are AD, Vascular dementia (VD), dementia with Lewy bodies and frontotemporal dementia. The most common reported cause of dementia is AD [3] followed by VD [22]. VD is secondary to both large and small vessel dysfunction leading to altered cerebral perfusion, cerebrovascular reactivity, and blood brain barrier (BBB) integrity [23,24]. ...
Many people living with dementia and cognitive impairment has dysfunctional mitochondrial and insulin-glucose metabolism resembling type 2 diabetes mellitus and old age. Evidence from human trials shows that nutritional interventions and anti-diabetic medicines that target nutrient-sensing pathways overcome these deficits in glucose and energy metabolism and can improve cognition and/or reduce symptoms of dementia. The liver is the main organ that mediates the systemic effects of diets and many diabetic medicines; therefore, it is an intermediate target for such dementia interventions. A challenge is the efficacy of these treatments in older age. Solutions include the targeted hepatic delivery of diabetic medicines using nanotechnologies and titration of macronutrients to optimize hepatic energy metabolism.
... First, our PheWAS was restricted by the available variables from the UKB database. Variables such as air pollution and blood glucose measures were not included, although they have been previously found to be associated with AD (43)(44)(45)(46). Second, because PheWAS looks for phenotypes that are associated with genetic architecture of AD, our study was less likely to uncover AD risk factors that have no or a weak genetic link to the disease. ...
Background
Considerable uncertainty remains regarding associations of multiple risk factors with Alzheimer’s disease (AD). We aimed to systematically screen and validate a wide range of potential risk factors for AD.
Methods and Materials
Among 502,493 participants from the UK Biobank (UKB), baseline data were extracted for 4171 factors spanning ten different categories. Phenome-wide association analyses (PheWAS) and time-to-event analyses were conducted to identify factors associated with both polygenic risk scores for AD (AD-PRS) and AD diagnosis at follow-up. We performed Two-sample Mendelian randomization (MR) analysis to further assess their potential causal relationships with AD and imaging association analysis to discover underlying mechanisms.
Results
We identified 39 factors significantly associated with both AD-PRS and risk of incident AD, where higher levels of education, body size, basal metabolic rate, fat-free mass, computer use, and cognitive functions were associated with a decreased risk of developing AD, and food selective intake and more outdoor exposures with an increased risk of developing AD. The identified factors were also associated with AD-related brain structures including hippocampus, entorhinal cortex and inferior/middle temporal cortex, and 21 of them were further supported by MR evidence.
Conclusions
This study, for the first time, comprehensively and rigorously assessed the effects of wide-ranging risk factors on AD. Strong evidence was found for body fat-free mass, basal metabolic rate, computer use, food selective intake, and outdoor exposures as new risk factors for AD. Integration of genetic, clinical, and neuroimaging information may help prioritize risk factors and prevention targets for AD.
