Format

Send to

Choose Destination
Biochem Pharmacol. 2014 Apr 15;88(4):548-59. doi: 10.1016/j.bcp.2013.12.012. Epub 2013 Dec 28.

Brain metabolic dysfunction at the core of Alzheimer's disease.

Author information

1
Departments of Pathology (Neuropathology), Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Neurology, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Neurosurgery, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA; Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA. Electronic address: Suzanne_DeLaMonte_MD@Brown.edu.
2
Departments of Medicine, Rhode Island Hospital and the Warren Alpert Medical School of Brown University, Providence, RI, USA.

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.

KEYWORDS:

Advanced glycation end-products; Alzheimer's disease; Ceramides; Insulin resistance; Lifestyle; Metabolic syndrome; N-Nitrosodiethylamine; Nitrosamine; Nitrosamines; Non-alcoholic fatty liver disease; Obesity; Reactive nitrogen species; Streptozotocin; Type 3 diabetes

PMID:
24380887
PMCID:
PMC4550323
DOI:
10.1016/j.bcp.2013.12.012
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center