Abstract
Most patients with Alzheimer's disease (AD) present decreased levels of melatonin, a day-night rhythm-related hormone. To investigate the role of melatonin deficiency in AD, we used constant illumination to interrupt melatonin metabolism and measured some of the AD-like alterations in rats. Concomitant with decreased serum melatonin, the rats developed spatial memory deficits, tau hyperphosphorylation at multiple sites, activation of glycogen synthase kinase-3 and protein kinase A, as well as suppression of protein phosphatase-1. Prominent oxidative damage and organelle lesions, demonstrated by increased expression of endoplasmic reticulum (ER) stress-related proteins including BiP/GRP78 and CHOP/GADD153, decreased number of rough ER and free ribosome, thinner synapses, and increased superoxide dismutase and monoamine oxidase were also observed in the light exposed rats. Simultaneous supplement of melatonin partially arrested the behavioral and molecular impairments. It is suggested that melatonin deficiency may be an upstream effector responsible for the AD-like behavioral and molecular pathologies with ER stress-involved mechanisms.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Alzheimer Disease / blood
-
Alzheimer Disease / complications
-
Alzheimer Disease / pathology*
-
Alzheimer Disease / prevention & control*
-
Animals
-
Antioxidants / therapeutic use*
-
Behavior, Animal
-
Cyclic AMP-Dependent Protein Kinases / metabolism
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Dose-Response Relationship, Radiation
-
Endoplasmic Reticulum / drug effects
-
Endoplasmic Reticulum / pathology*
-
Endoplasmic Reticulum / ultrastructure
-
Glycogen Synthase Kinase 3 / metabolism
-
Hippocampus / drug effects
-
Hippocampus / enzymology
-
Hippocampus / ultrastructure
-
Lighting / adverse effects
-
Male
-
Maze Learning / drug effects
-
Maze Learning / physiology
-
Melatonin / blood
-
Melatonin / therapeutic use*
-
Microscopy, Immunoelectron / methods
-
Monoamine Oxidase / metabolism
-
Phosphoric Monoester Hydrolases / metabolism
-
Rats
-
Rats, Wistar
-
Reaction Time / drug effects
-
Reaction Time / radiation effects
-
Superoxide Dismutase / metabolism
-
tau Proteins / metabolism
Substances
-
Antioxidants
-
tau Proteins
-
Superoxide Dismutase
-
Monoamine Oxidase
-
Cyclic AMP-Dependent Protein Kinases
-
Glycogen Synthase Kinase 3
-
polyphosphoinositide phosphatase
-
Phosphoric Monoester Hydrolases
-
Melatonin