Mark A. Smith (Case Western Reserve University), J. Wes Ashford (Stanford University)
Submitted June 26, 2008
Whitmer et al. demonstrated a significant correlation between mid-life obesity and dementia later in life and suggested that visceral adipocyte-derived factors may be neurotoxic, contributing to the slow deterioration of the CNS. [1]
However, it has been shown that some of these factors including leptin may be beneficial to neurons. Leptin is capable of reducing the brain Aß load [8], is neuroprotective and improves cognitive performance of aged rodents. [9]
Obesity is often characterized by some form of leptin resistance that may be attributable to CRP (C-reactive protein), which is elevated in obesity. [10] CRP can bind to leptin preventing its binding to the leptin receptor. Therefore, obese subjects may be deprived from leptin's beneficial action, propagating obesity and neurodegeneration.
It has also been documented that obese individuals who eventually developed AD may experience a loss in weight prior to the onset of dementia. [11] A gradual selective neuronal loss in the hippocampus, hypothalamus, or both due to the absence of centrally acting leptin may lead to disturbances in appetite.
In AD patients, leptin levels are reduced whereas blood CRP levels are normal so leptin therapy may benefit AD patients. Additional benefits may include ability to increase insulin sensitivity and alleviate insulin resistance which are common in AD.
9. Harvey J. Leptin: a diverse regulator of neuronal function. J Neurochem 2007;100:307-313.
10. Chen K, Li F, Li J, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 2006;12:425-432.
11. Gustafson S. Adiposity indices and dementia. Lancet Neurol 2006;5:713-720.
Disclosure: Dr. Tezapsidis is the founder of Neurotez, Inc., a private CNS biotechnology corporation (www.neurotez.com) that is pursuing leptin as a novel therapeutic for AD. Drs. Mark Smith and Wes Ashford are affiliated with Neurotez, Inc.
Whitmer et al. demonstrated a significant correlation between mid-life obesity and dementia later in life and suggested that visceral adipocyte-derived factors may be neurotoxic, contributing to the slow deterioration of the CNS. [1]
However, it has been shown that some of these factors including leptin may be beneficial to neurons. Leptin is capable of reducing the brain Aß load [8], is neuroprotective and improves cognitive performance of aged rodents. [9]
Obesity is often characterized by some form of leptin resistance that may be attributable to CRP (C-reactive protein), which is elevated in obesity. [10] CRP can bind to leptin preventing its binding to the leptin receptor. Therefore, obese subjects may be deprived from leptin's beneficial action, propagating obesity and neurodegeneration.
It has also been documented that obese individuals who eventually developed AD may experience a loss in weight prior to the onset of dementia. [11] A gradual selective neuronal loss in the hippocampus, hypothalamus, or both due to the absence of centrally acting leptin may lead to disturbances in appetite.
In AD patients, leptin levels are reduced whereas blood CRP levels are normal so leptin therapy may benefit AD patients. Additional benefits may include ability to increase insulin sensitivity and alleviate insulin resistance which are common in AD.
References
8. Fewlass DC, Noboa K, Pi-Sunyer FX, Johnston JM, Yan SD, Tezapsidis N. Obesity-related leptin regulates Alzheimer's Abeta. Faseb J 2004;18:1870-1878.
9. Harvey J. Leptin: a diverse regulator of neuronal function. J Neurochem 2007;100:307-313.
10. Chen K, Li F, Li J, et al. Induction of leptin resistance through direct interaction of C-reactive protein with leptin. Nat Med 2006;12:425-432.
11. Gustafson S. Adiposity indices and dementia. Lancet Neurol 2006;5:713-720.
Disclosure: Dr. Tezapsidis is the founder of Neurotez, Inc., a private CNS biotechnology corporation (www.neurotez.com) that is pursuing leptin as a novel therapeutic for AD. Drs. Mark Smith and Wes Ashford are affiliated with Neurotez, Inc.