TY - JOUR
T1 - Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer's disease pathology in mice
AU - Djogo, Nevena
AU - Jakovcevski, Igor
AU - Müller, Christian
AU - Lee, Hyun Joon
AU - Xu, Jin Chong
AU - Jakovcevski, Mira
AU - Kügler, Sebastian
AU - Loers, Gabriele
AU - Schachner, Melitta
N1 - Funding Information:
We are grateful to Emanuela Szpotowicz for excellent technical assistance, to Isabelle Aubert, Andrey Irintchev, Carsten Schmidt for critical reading of the manuscript, and Southeast Europe Cooperation Hamburg for support. We thank Mathias Jucker for the generous gift of APPPS1 mice. Authors declare no conflict of interest. This work was supported by grants from the New Jersey Commission for Spinal Cord Research and Li Ka-Shing Foundation (to M.S.).
PY - 2013/8
Y1 - 2013/8
N2 - Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of elderly dementia. In an effort to contribute to the potential of molecular approaches to reduce degenerative processes we have tested the possibility that the neural adhesion molecule L1 ameliorates some characteristic cellular and molecular parameters associated with the disease in a mouse model of AD. Three-month-old mice overexpressing mutated forms of amyloid precursor protein and presenilin-1 under the control of a neuron-specific promoter received an injection of adeno-associated virus encoding the neuronal isoform of full-length L1 (AAV-L1) or, as negative control, green fluorescent protein (AAV-GFP) into the hippocampus and occipital cortex. Four months after virus injection, the mice were analyzed for histological and biochemical parameters of AD. AAV-L1 injection decreased the Aβ plaque load, levels of Aβ42, Aβ42/40 ratio and astrogliosis compared with AAV-GFP controls. AAV-L1 injected mice also had increased densities of inhibitory synaptic terminals on pyramidal cells in the hippocampus when compared with AAV-GFP controls. Numbers of microglial cells/macrophages were similar in both groups, but numbers of microglial cells/macrophages per plaque were increased in AAV-L1 injected mice. To probe for a molecular mechanism that may underlie these effects, we analyzed whether L1 would directly and specifically interact with Aβ. In a label-free binding assay, concentration dependent binding of the extracellular domain of L1, but not of the close homolog of L1 to Aβ40 and Aβ42 was seen, with the fibronectin type III homologous repeats 1-3 of L1 mediating this effect. Aggregation of Aβ42 in vitro was reduced in the presence of the extracellular domain of L1. The combined observations indicate that L1, when overexpressed in neurons and glia, reduces several histopathological hallmarks of AD in mice, possibly by reduction of Aβ aggregation. L1 thus appears to be a candidate molecule to ameliorate the pathology of AD, when applied in therapeutically viable treatment schemes.
AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of elderly dementia. In an effort to contribute to the potential of molecular approaches to reduce degenerative processes we have tested the possibility that the neural adhesion molecule L1 ameliorates some characteristic cellular and molecular parameters associated with the disease in a mouse model of AD. Three-month-old mice overexpressing mutated forms of amyloid precursor protein and presenilin-1 under the control of a neuron-specific promoter received an injection of adeno-associated virus encoding the neuronal isoform of full-length L1 (AAV-L1) or, as negative control, green fluorescent protein (AAV-GFP) into the hippocampus and occipital cortex. Four months after virus injection, the mice were analyzed for histological and biochemical parameters of AD. AAV-L1 injection decreased the Aβ plaque load, levels of Aβ42, Aβ42/40 ratio and astrogliosis compared with AAV-GFP controls. AAV-L1 injected mice also had increased densities of inhibitory synaptic terminals on pyramidal cells in the hippocampus when compared with AAV-GFP controls. Numbers of microglial cells/macrophages were similar in both groups, but numbers of microglial cells/macrophages per plaque were increased in AAV-L1 injected mice. To probe for a molecular mechanism that may underlie these effects, we analyzed whether L1 would directly and specifically interact with Aβ. In a label-free binding assay, concentration dependent binding of the extracellular domain of L1, but not of the close homolog of L1 to Aβ40 and Aβ42 was seen, with the fibronectin type III homologous repeats 1-3 of L1 mediating this effect. Aggregation of Aβ42 in vitro was reduced in the presence of the extracellular domain of L1. The combined observations indicate that L1, when overexpressed in neurons and glia, reduces several histopathological hallmarks of AD in mice, possibly by reduction of Aβ aggregation. L1 thus appears to be a candidate molecule to ameliorate the pathology of AD, when applied in therapeutically viable treatment schemes.
KW - APPPS1 mice
KW - Adeno-associated virus serotype 5
KW - Alzheimer's disease
KW - Amyloid beta peptides
KW - Amyloid precursor protein
KW - Astrogliosis
KW - Hippocampus
KW - Neural cell adhesion molecule L1
KW - Synaptic terminals
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UR - http://www.scopus.com/inward/citedby.url?scp=84878156206&partnerID=8YFLogxK
U2 - 10.1016/j.nbd.2013.04.014
DO - 10.1016/j.nbd.2013.04.014
M3 - Article
C2 - 23639788
AN - SCOPUS:84878156206
VL - 56
SP - 104
EP - 115
JO - Neurobiology of Disease
JF - Neurobiology of Disease
SN - 0969-9961
ER -