Differential accumulation of secreted AbetaPP metabolites in ocular fluids.
Amyloid-beta (Abeta) accumulates in several types of retinal degeneration and in Alzheimer's disease (AD), but its source has been unclear. We detected the neuronal 695 amino acid form of amyloid-beta protein precursor (AbetaPP) in the normal retina and AbetaPP751 in the retinal pigment epithelium (RPE) and anterior eye tissues. Similar to the brain, alpha- and beta-secretases cleaved AbetaPP to soluble derivatives (sAbetaPP) alpha or beta and membrane-bound C-terminal fragments alpha or beta in the retina and RPE. Levels of sAbetaPP were particularly high in the vitreous and low in aqueous humor revealing a molecular barrier for AbetaPP. In contrast, Abeta40 and Abeta42 levels were only 50% lower in the aqueous than the vitreous humor, indicating relatively barrier-free movement of Abeta. These studies demonstrated a relatively high yield of AbetaPP and Abeta in the ocular fluids, which may serve as a trackable marker for AD. In addition, failure of free clearance from the eye may trigger retina degeneration in a manner similar to Abeta-related neurodegeneration in AD.
Prakasam
Annamalai
A
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Muthuswamy
Anusuya
A
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Ablonczy
Zsolt
Z
Department of Ophthalmology, Medical University of South Carolina, Storm Eye Institute, Charleston, SC, USA.
Greig
Nigel H
NH
Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
Fauq
Abdul
A
Department of Neurosciences, Mayo Clinic, Jacksonville, FL, USA.
Rao
Kosagisharaf Jagannatha
KJ
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Pappolla
Miguel A
MA
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
Sambamurti
Kumar
K
Department of Neurosciences, Medical University of South Carolina, Charleston, SC, USA.
D000595:Amino Acid Sequence; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001082:Aqueous Humor / Q000737:chemistry / Q000378:metabolism; D001826:Body Fluids / Q000378:metabolism; D001923:Brain Chemistry / Q000502:physiology; D002417:Cattle; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology; D003513:Cycloheximide / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005123:Eye / Q000033:anatomy & histology / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012160:Retina / Q000378:metabolism / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000187:drug effects / Q000378:metabolism; D014822:Vitreous Body / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D011500:Protein Synthesis Inhibitors; D003513:Cycloheximide; D053829:Amyloid Precursor Protein Secretases