Efficacy and safety of immunization with phosphorylated tau against neurofibrillary tangles in mice.

Abstract

As an abnormally folded and aggregated protein, tau composed of neurofibrillary tangles (NFTs) in Alzheimer's disease and other tauopathies seems to be a candidate for immunotherapy. Yet, the encephalitogenicity of full-length tau protein, recently reported by us in immunized mice, demands to carefully and selectively target pathological tau and address both efficacy (anti-NFT effect) and safety (free of encephalitis). We immunized NFT mice with NFT-related phosphorylated (phos) tau peptides, using an immunization protocol aimed to predispose a proinflammatory milieu in CNS as a set up to detect biohazard, an approach we used when the neurotoxicity of full-length tau was detected [use of complete Freund adjuvant (CFA) with pertussis toxin (PT)]. A decrease of about 40% in NFT burden in CNS was demonstrated and was accompanied with an increase in microglial burden. Anti-phos-tau antibodies were detected in serum and blood vessels in the CNS, while no encephalitogenicity (free of clinical neurological deficits, of adverse effects on brain inflammatory cells and of axonal damage) was recorded. The level of the lysosomal proteases, cathepsins D and L, was affected in the immunized mice suggesting the possible involvement of the lysosomal system in the decrease of NFTs. The robust anti-NFT effect and the lack of encephalitogenicity in NFT mice immunized with phos-tau peptides, even though CFA with PT was included in vaccine, point to their anti-NFT therapeutic potential.

• Authors: Moran Boimel, Nikolaos Grigoriadis, Athanasios Lourbopoulos, Esther Haber, Oded Abramsky, Hanna Rosenmann
• Journal: Experimental neurology (Exp Neurol) Vol. 224 Issue 2 Pg. 472-85 (Aug 2010) ISSN: 1090-2430 [Electronic] United States
• PMID: 20546729 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: (c) 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antibodies
• Peptide Fragments
• Phosphoproteins
• Vaccines, Synthetic
• tau Proteins
• Peptide Hydrolases
• Cathepsin L
• Cathepsin D

Topics

• Animals
• Antibodies (blood)
• Astrocytes (immunology, pathology)
• Brain (metabolism, pathology)
• Cathepsin D (metabolism)
• Cathepsin L (metabolism)
• Encephalitis (chemically induced)
• Female
• Immunization
• Lysosomes (enzymology)
• Mice
• Mice, Transgenic
• Microglia (immunology, pathology)
• Neurofibrillary Tangles (immunology, pathology)
• Neurons (immunology, pathology)
• Peptide Fragments (adverse effects, immunology)
• Peptide Hydrolases (metabolism)
• Phosphoproteins (adverse effects, therapeutic use)
• Tauopathies (immunology, pathology, therapy)
• Vaccines, Synthetic (adverse effects, immunology)
• tau Proteins (adverse effects, therapeutic use)