Proteolytic antibody light chains alter β-amyloid aggregation and prevent cytotoxicity

Ruitian Liu, Chad McAllister, Yuri L Lyubchenko, Michael R. Sierks

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

β-Amyloid (Aβ, a peptide generated by proteolytic cleavage of the amyloid precursor protein (APP), is a major constituent of the neuritic plaques associated with Alzheimer's disease (AD). Up-regulation of α-secretase, which can hydrolyze Aβ between Lys16 and Leu17, has been proposed as a potential therapeutic strategy in the treatment of AD. Previously, we identified two light-chain antibody fragments that had proteolytic activity against Aβ, one with α-secretase-like activity and one with carboxypeptidase-like activity. Here we show that cleavage of Aβ40 by hk14, the light-chain antibody having carboxypeptidase-like activity, alters aggregation of Aβ and neutralizes any cytotoxic effects of the peptide. Cleavage of Aβ40 with c23.5, the light chain having α-secretase-like cleavage, substantially increases the aggregation rate of Aβ however, it does not show any corresponding increase in cytotoxicity. The increase in aggregation resulting from hydrolysis by c23.5 can be attributed to the decreased solubility of the hydrolyzed products relative to the parent Aβ40, primarily the Aβ-40 fragment. These results demonstrate that antibody fragment mediated proteolytic degradation of Aβ peptide can be a potential therapeutic route to control Aβ aggregation and toxicity in vivo. Our results also suggest that increasing α-secretase activity as a therapeutic route must be approached with some caution because this can lead to a substantial increase in aggregation.

Original languageEnglish (US)
Pages (from-to)9999-10007
Number of pages9
JournalBiochemistry
Volume43
Issue number31
DOIs
StatePublished - Aug 10 2004

Fingerprint

Amyloid Precursor Protein Secretases
Cytotoxicity
Amyloid
Agglomeration
Carboxypeptidases
Light
Immunoglobulin Fragments
Antibodies
Peptides
Alzheimer Disease
Amyloid beta-Protein Precursor
Amyloid Plaques
Solubility
Hydrolysis
Up-Regulation
Therapeutics
Toxicity
Degradation

ASJC Scopus subject areas

  • Biochemistry

Cite this

Proteolytic antibody light chains alter β-amyloid aggregation and prevent cytotoxicity. / Liu, Ruitian; McAllister, Chad; Lyubchenko, Yuri L; Sierks, Michael R.

In: Biochemistry, Vol. 43, No. 31, 10.08.2004, p. 9999-10007.

Research output: Contribution to journalArticle

Liu, Ruitian ; McAllister, Chad ; Lyubchenko, Yuri L ; Sierks, Michael R. / Proteolytic antibody light chains alter β-amyloid aggregation and prevent cytotoxicity. In: Biochemistry. 2004 ; Vol. 43, No. 31. pp. 9999-10007.
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