Research Article Details
| Article ID: | A22653 |
| PMID: | 24380887 |
| Source: | Biochem Pharmacol |
| Title: | Brain metabolic dysfunction at the core of Alzheimer's disease. |
| Abstract: | Growing evidence supports the concept that Alzheimer's disease (AD) is fundamentally a metabolic disease with molecular and biochemical features that correspond with diabetes mellitus and other peripheral insulin resistance disorders. Brain insulin/IGF resistance and its consequences can readily account for most of the structural and functional abnormalities in AD. However, disease pathogenesis is complicated by the fact that AD can occur as a separate disease process, or arise in association with systemic insulin resistance diseases, including diabetes, obesity, and non-alcoholic fatty liver disease. Whether primary or secondary in origin, brain insulin/IGF resistance initiates a cascade of neurodegeneration that is propagated by metabolic dysfunction, increased oxidative and ER stress, neuro-inflammation, impaired cell survival, and dysregulated lipid metabolism. These injurious processes compromise neuronal and glial functions, reduce neurotransmitter homeostasis, and cause toxic oligomeric pTau and (amyloid beta peptide of amyloid beta precursor protein) AβPP-Aβ fibrils and insoluble aggregates (neurofibrillary tangles and plaques) to accumulate in brain. AD progresses due to: (1) activation of a harmful positive feedback loop that progressively worsens the effects of insulin resistance; and (2) the formation of ROS- and RNS-related lipid, protein, and DNA adducts that permanently damage basic cellular and molecular functions. Epidemiologic data suggest that insulin resistance diseases, including AD, are exposure-related in etiology. Furthermore, experimental and lifestyle trend data suggest chronic low-level nitrosamine exposures are responsible. These concepts offer opportunities to discover and implement new treatments and devise preventive measures to conquer the AD and other insulin resistance disease epidemics. |
| DOI: | 10.1016/j.bcp.2013.12.012 |
| Strategy ID | Therapy Strategy | Synonyms | Therapy Targets | Therapy Drugs | |
|---|---|---|---|---|---|
| S01 | Improve insulin resistance | insulin sensitizer; insulin resistance; glucose tolerance | Biguanide: increases 5-AMP activated protein kinase signaling; SGLT-2 inhibitor; Thiazalidinedione: selective PPAR-γ agonists; GLP-1 agonist | Metformin; Empagliflozin; Canagliflozin; Rosiglitazone; Pioglitazone; Liraglutide | Details |
| S02 | Enhance lipid metabolism | triglyceride-lowering; lipid tolerance; lipid metabolism | 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitor; Decreases intestinal cholesterol absorption; FXR agonist; ACC inhibitor; FAS inhibitor; DGAT2 inhibitor; SCD-1 inhibitor | Atorvastatin; Ezetimibe; Obeticholic Acid; GS-9674; GS-0976; TVB-2640; IONIS-DGAT2rx; Aramchol; | Details |
| Diseases ID | DO ID | Disease Name | Definition | Class | |
|---|---|---|---|---|---|
| I05 | 9352 | Type 2 diabetes mellitus | A diabetes that is characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both. A diabetes mellitus that is characterized by high blood sugar, insulin resistance, and relative lack of insulin. http://en.wikipedia.org/wiki/Diabetes, http://en.wikipedia.org/wiki/Diabetes_mellitus_type_2 | disease of metabolism/inherited metabolic disorder/ carbohydrate metabolic disorder/glucose metabolism disease/diabetes/ diabetes mellitus | Details |
| I14 | 9970 | Obesity | An overnutrition that is characterized by excess body fat, traditionally defined as an elevated ratio of weight to height (specifically 30 kilograms per meter squared), has_material_basis_in a multifactorial etiology related to excess nutrition intake, decreased caloric utilization, and genetic susceptibility, and possibly medications and certain disorders of metabolism, endocrine function, and mental illness. https://en.wikipedia.org/wiki/Obesity | disease of metabolism/acquired metabolic disease/ nutrition disease/overnutrition | Details |
| Drug ID | Drug Name | Type | DrugBank ID | Targets | Category | Latest Progress | |
|---|---|---|---|---|---|---|---|
| D579 | Emfilermin | Miscellany | -- | adipocytes | Enhance lipid metabolism | Under investigation | Details |
| D182 | Insulin | Biological drug | DB00030 | INSR agonist; CPE modulator&product of | -- | Under clinical trials | Details |
| D316 | S-adenosyl-L-methionine | Chemical drug | DB00118 | GNMT cofactor | Antiviral | Under clinical trials | Details |
| D094 | Cysteamine | Chemical drug | DB00847 | GSS stimulant | Renal drug | Under clinical trials | Details |
| D095 | Cysteamine bitartrate | Chemical drug | DB00847 | -- | -- | Under clinical trials | Details |