ABSTRACT
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.
Subject(s)
Amyloid beta-Protein Precursor/metabolism , Eye/metabolism , Amino Acid Sequence , Amyloid Precursor Protein Secretases/metabolism , Animals , Aqueous Humor/chemistry , Aqueous Humor/metabolism , Body Fluids/metabolism , Brain Chemistry/physiology , Cattle , Central Nervous System/metabolism , Central Nervous System/pathology , Cycloheximide/pharmacology , Enzyme-Linked Immunosorbent Assay , Eye/anatomy & histology , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Protein Synthesis Inhibitors/pharmacology , Retina/metabolism , Retina/pathology , Retinal Pigment Epithelium/drug effects , Retinal Pigment Epithelium/metabolism , Vitreous Body/metabolismABSTRACT
Emerging evidences on the nuclear localization of alpha-Synuclein in neurons and a close look in to its primary sequence/structural organization led us to examine its DNA binding ability. Subsequently, we first time demonstrated the interaction of DNA with alpha-Synuclein which was also confirmed by others. We recently showed that double-stranded oligos induce partial folding in alpha-Synuclein and promote its aggregation, where as single-strand circular DNA and supercoiled plasmid DNA induced a helix-rich conformation and protected the protein from fibrillation. In turn, alpha-Synuclein modulates DNA conformation from B- to an altered B-form, which may affect DNA transactions. Interestingly, amyloid-beta peptides and prion proteins implicated in Alzheimer's disease and Prion diseases respectively, were also shown to have DNA binding activity which suggests that DNA binding may be a common property of many amyloidogenic proteins associated with various neurodegenerative disorders. In this review, we debate the biological significance of DNA-alpha-Synuclein interactions; it's beneficial vs. toxic role in relevance to Parkinson's disease.
Subject(s)
DNA/metabolism , Parkinson Disease/metabolism , alpha-Synuclein/metabolism , Animals , Cell Nucleus/metabolism , DNA/chemistry , DNA/genetics , Humans , Models, Biological , Nucleic Acid Conformation , Parkinson Disease/genetics , Parkinson Disease/pathology , Protein Binding , Protein Folding , alpha-Synuclein/chemistryABSTRACT
A close association between brain metal dishomeostasis and the onset and/or progression of Alzheimer's disease (AD) has been clearly established in a number of studies, although the underlying biochemical mechanisms remain obscure. This observation renders chelation therapy an attractive pharmacological option for the treatment of this disease. However, a number of requirements must be fulfilled in order to adapt chelation therapy to AD so that the term "metal targeted strategies" seems now more appropriate. Indeed, brain metal redistribution rather than brain metal scavenging and removal is the major goal of this type of intervention. The most recent developments in metal targeted strategies for AD will be discussed using, as useful examples, clioquinol, curcumin, and epigallocatechin, and the future perspectives will also be outlined.
