A mitocentric view of Alzheimer's disease suggests multi-faceted treatments.
Alzheimer's disease (AD) is defined by senile plaques made of amyloid-beta peptide (Abeta), neurofibrillary tangles made of hyperphosphorylated tau proteins, and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g., genetic mutations lead to high Abeta1-42 or hyperphosphorylated tau proteins). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in glucose metabolism/mitochondrial function/oxidative stress (GMO) are an invariant feature of AD and occur at an early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Abnormal GMO can lead to plaques, tangles, and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting mitochondria may ameliorate abnormalities in plaques, tangles, calcium homeostasis, and cognition that comprise AD.
Gibson
Gary E
GE
Weill Cornell Medical College/Burke Medical Research Institute, White Plains, NY, USA. ggibson@med.cornell.edu
Shi
Qingli
Q
D000544:Alzheimer Disease / Q000209:etiology* / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000473:pathology / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D003071:Cognition / Q000502:physiology; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D044882:Glucose Metabolism Disorders / Q000150:complications; D006801:Humans; D008928:Mitochondria / Q000378:metabolism*; D028361:Mitochondrial Diseases / Q000150:complications; D018384:Oxidative Stress / Q000235:genetics / Q000502:physiology
D016229:Amyloid beta-Peptides; D005947:Glucose; D002118:Calcium
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