TY - JOUR
T1 - Bispecific Antibody Fragment Targeting APP and Inducing α-Site Cleavage Restores Neuronal Health in an Alzheimer’s Mouse Model
AU - He, Ping
AU - Xin, Wei
AU - Schulz, Philip
AU - Sierks, Michael R.
N1 - Funding Information:
We thank Dr. Hailan Yao from the Roskamp Institute for providing some of antibodies.
Publisher Copyright:
© 2019, Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - The amyloid β (Aβ) peptide, correlated with development of Alzheimer’s disease (AD), is produced by sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Alternative proteolytic cleavage of APP by α-secretase prevents formation of Aβ peptide and produces a neuroprotective protein, a soluble fragment of APPα (sAPPα). We previously generated a single-chain variable domain antibody fragment (scFv) that binds APP at the β-secretase cleavage site and blocks cleavage of APP (iBsec1), and a second scFv which has been engineered to have α-secretase-like activity that increases α-secretase cleavage of APP (Asec1a) and showed that a bispecific antibody (Diab) combining both iBsec1 and Asec1a constructs protects mammalian cells from oxidative stress. Here, we show that the diabody is an effective therapeutic agent in a mouse model of AD. An apolipoprotein B (ApoB) binding domain peptide was genetically added to the diabody to facilitate transfer across the blood-brain barrier, and a recombinant human adeno-associated virus 2/8 (rAAV2/8) was used as a vector to express the gene constructs in a APP/PS1 mouse model of AD. The diabody increased levels of sAPPα, decreased Aβ deposits and levels of oligomeric Aβ, increased neuronal health as indicated by MAP2 and synaptophysin staining, increased hippocampal neurogenesis, and most importantly dramatically increased survival rates compared with untreated mice or mice treated only with the β-secretase inhibitor. These results indicate that altering APP processing to inhibit β-site activity while simultaneously promoting α-secretase processing provides substantially increased neuronal benefits compared with inhibition of β-secretase processing alone and represents a promising new therapeutic approach for treating AD.
AB - The amyloid β (Aβ) peptide, correlated with development of Alzheimer’s disease (AD), is produced by sequential proteolytic cleavage of the amyloid precursor protein (APP) by β- and γ-secretases. Alternative proteolytic cleavage of APP by α-secretase prevents formation of Aβ peptide and produces a neuroprotective protein, a soluble fragment of APPα (sAPPα). We previously generated a single-chain variable domain antibody fragment (scFv) that binds APP at the β-secretase cleavage site and blocks cleavage of APP (iBsec1), and a second scFv which has been engineered to have α-secretase-like activity that increases α-secretase cleavage of APP (Asec1a) and showed that a bispecific antibody (Diab) combining both iBsec1 and Asec1a constructs protects mammalian cells from oxidative stress. Here, we show that the diabody is an effective therapeutic agent in a mouse model of AD. An apolipoprotein B (ApoB) binding domain peptide was genetically added to the diabody to facilitate transfer across the blood-brain barrier, and a recombinant human adeno-associated virus 2/8 (rAAV2/8) was used as a vector to express the gene constructs in a APP/PS1 mouse model of AD. The diabody increased levels of sAPPα, decreased Aβ deposits and levels of oligomeric Aβ, increased neuronal health as indicated by MAP2 and synaptophysin staining, increased hippocampal neurogenesis, and most importantly dramatically increased survival rates compared with untreated mice or mice treated only with the β-secretase inhibitor. These results indicate that altering APP processing to inhibit β-site activity while simultaneously promoting α-secretase processing provides substantially increased neuronal benefits compared with inhibition of β-secretase processing alone and represents a promising new therapeutic approach for treating AD.
KW - Alzheimer’s disease
KW - Amyloid precursor protein
KW - Neuron
KW - Single-chain antibody
KW - Transgenic mice
KW - α-Secretase
KW - β-Secretase
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U2 - 10.1007/s12035-019-1597-z
DO - 10.1007/s12035-019-1597-z
M3 - Article
C2 - 31041656
AN - SCOPUS:85065260601
SN - 0893-7648
VL - 56
SP - 7420
EP - 7432
JO - Molecular Neurobiology
JF - Molecular Neurobiology
IS - 11
ER -