Acute and chronic effects of intravitreally injected beta-amyloid on the neurotransmitter system in the retina.
The potential cytotoxic effect of aggregated Abeta(1-42) to neurons that express classical neurotransmitters, including acetylcholine, gamma-amino butyric acid, catecholamines and serotonin was assessed. The cholinergic system has been the central focus of the therapeutic drug strategies in amyloid-depositing pathologies such as Alzheimer's disease. Aggregated Abeta(1-42) has a multisystem cytotoxic effect causing non-specific reduction in immunoreactivity, dysfunction, or loss of retinal nerve cells. The extent of this was investigated using immunocytochemistry, TUNEL staining for apoptosis, and measurement of cell density as well as retinal surface area. There was a differential acute and/or chronic effect of Abeta on choline acetyltransferase, gamma-aminobutyric acid and 5-tryptamine hydroxylase systems, observed with the increasing time course of 6h to 5 months, and a bilateral/systemic effect. In contrast, the overall pattern of catecholaminergic system, as revealed by tyrosine hydroxylase immunoreactivity of the retina, appears to have remained relatively unaffected by Abeta (however this may reflect neuronal loss due to reduction in the retinal surface). This is the first in vivo evidence in a CNS model to show that not only all major neurotransmitter systems are differentially affected by Abeta aggregates but the effect may vary from one transmitter system to another under the same experimental conditions in situ and in a dose- and time-dependent manner.
Aruoma
Okezie I
OI
Department of Pharmaceutical and Biomedical Sciences, Touro College of Pharmacy, New York, NY 10027, USA. okezie.aruoma@touro.edu
Jen
Sheila S M
SS
Watts
Helena R
HR
George
Joseph
J
Gentleman
Stephen M
SM
Anderson
Peter J B
PJ
Jen
Ling-Sun
LS
D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008845:Microinjections; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D018377:Neurotransmitter Agents / Q000378:metabolism*; D010275:Parasympathetic Nervous System / Q000187:drug effects / Q000502:physiology; D020419:Photoreceptor Cells, Vertebrate / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D012165:Retinal Ganglion Cells / Q000187:drug effects; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D014822:Vitreous Body; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D016229:Amyloid beta-Peptides; D005904:Glial Fibrillary Acidic Protein; D018377:Neurotransmitter Agents; D005680:gamma-Aminobutyric Acid; D003577:Cytochrome P-450 Enzyme System; D014446:Tyrosine 3-Monooxygenase; C407366:tryptamine 5-hydroxylase; D002795:Choline O-Acetyltransferase