An intraperitoneally administered pentapeptide protects against Abeta (1-42) induced neuronal excitation in vivo.
The underlying cause of Alzheimer's disease (AD) is thought to be the accumulation and aggregation of a misfolded protein, amyloid-beta (Abeta). A promising strategy against AD is the application of protective, peptide-based neuroprotective agents that selectively bind to Abeta. We recently described a pentapeptide, LPYFDa, which recognizes Abeta (1-42) and protects neurons against the toxic effects of aggregated Abeta (1-42) both in vitro and in vivo. Our previous work indicated that the in vivo ejection of fibrillar Abeta (1-42) into the hippocampal CA1 region resulted in a massive increase in the NMDA-evoked neuronal firing rate. Our current aim was to study whether intraperitoneally administered LPYFDa is capable of protecting against the synaptotoxic action of fibrillar Abeta (1-42) administered by iontophoresis. Our investigations of the in vivo biodistribution of tritium-labelled LPYFDa and single-unit electrophysiology revealed that LPYFDa readily crosses the blood-brain barrier, and protects the synapses against the excitatory action of fibrillar Abeta (1-42) in a relatively wide temporal window in rat. This pentapeptide may serve as a lead compound for the design of novel drug candidates for the prevention of AD.
Juhász
Gábor
G
Department of Medical Chemistry, University of Szeged, Szeged, Hungary.
Márki
Arpád
A
Vass
Gabriella
G
Fülöp
Lívia
L
Budai
Dénes
D
Penke
Botond
B
Falkay
György
G
Szegedi
Viktor
V
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D004594:Electrophysiology; D018690:Excitatory Amino Acid Agonists / Q000008:administration & dosage / Q000494:pharmacology; D005110:Extracellular Space / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007478:Iontophoresis; D008297:Male; D046529:Microscopy, Electron, Transmission; D016202:N-Methylaspartate / Q000008:administration & dosage / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D009842:Oligopeptides / Q000493:pharmacokinetics* / Q000494:pharmacology*; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013569:Synapses / Q000187:drug effects; D014018:Tissue Distribution
D016229:Amyloid beta-Peptides; D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D009842:Oligopeptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); C539346:leucyl-prolyl-tyrosyl-phenylalanyl-aspartamide; D016202:N-Methylaspartate