[P‐183]: Blocking the apolipoprotein E/amyloid‐B interaction reduces amyloid‐B load in AD transgenic mice
Year: 2005
Type: article
Abstract: Presence of the apolipoprotein (apo) E4 allele is the major identified genetic risk factor for sporadic Alzheimer's disease (AD). All apoE isoforms (E2, E3, and E4) can bind amyloid-β (Aβ) and under certain conditions propagate the β-sheet content of Aβ peptides. The apoE4 isoform is most efficient at promoting fibril formation and Aβ deposition. Knock-out of the apoE gene in APP transgenic (Tg) AD mice resulted in a significant reduction of Aβ load and a virtual absence of fibrillar Aβ deposits, suggesting that neutralization of apo E's effect on Aβ fibrillogenesis and deposition could be a potential therapeutic approach for AD related brain amyloidosis. Our goal is to develop an inhibitor of the apoE/Aβ interaction suitable for in vivo application. We synthesized a peptide homologous to residues 12-28 of Aβ (the apoE binding site) with the valine at residue 18 substituted by a proline, using D-amino acids. These modifications render Aβ12-28P non-fibrillogenic and non-toxic. We have previously demonstrated in vitro that Aβ12-28P can effectively neutralize the promoting effect of apoE on Aβ fibrillogenesis and cytotoxicity in cell culture (Sadowski et al. AJP, 2004;165:937). Aβ12-28P is blood-brain-barrier permeable and its end-protected version has a serum half-life of 62.2±18min. The objective of this study was to test the in vivo activity of Aβ12-28P in AD Tg model mice. Female APP/PS1 Tg AD mice were treated with Aβ12-28P (1mg of peptide or placebo administered intraperitoneally) for five months starting from the age of two months, which is prior to the onset of detectable brain amyloid deposits. Treatment with Aβ12-28P resulted in a significant reduction of Aβ load: 51.6% in the neocortex, 40.0% in the hippocampus, and 49.2% in the cingulate/retropslenial cortex (p<0.01). Fibrillar Aβ, detected by Thioflavin-S staining, was reduced by 21.9%, 24.7%, and 28.9%, respectively (p<0.05). Levels of formic acid extracted Aβ1-40 and Aβ1-42 were decreased on ELISA measurements by 42.5% and 29.9%, respectively (p<0.01). No signs of toxicity or any autoimmune reaction were observed in treated animals. These results demonstrate that pharmacological blocking of the apoE/Aβ interaction may be used to prevent Aβ deposition in AD patients.
Source: Alzheimer s & Dementia
Institution: New York University
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W1979775698