Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice.
Brain-derived neurotrophic factor (BDNF) improves molecular, cellular, and behavioral measures of neural dysfunction in genetic models of Alzheimer's disease (Blurton-Jones et al., 2009; Nagahara et al., 2009). However, BDNF treatment after disease onset has not been reported to improve neuronal survival in these models. We now report prevention of neuronal loss with early life BDNF treatment in mutant mice expressing two amyloid precursor protein (APP) mutations associated with early-onset familial Alzheimer's disease. APP transgenic mice underwent lentiviral BDNF gene delivery into the entorhinal cortices at age 2 months and were examined 5 months later. BDNF-treated mice exhibited significant improvements in hippocampal-dependent contextual fear conditioning compared with control-treated APP mice (p < 0.05). Stereological analysis of entorhinal cortical cell number demonstrated ∼20% reductions in neuronal number in layers II-VI of the entorhinal cortex in untreated APP mutant mice compared with wild-type mice (p < 0.0001), and significant amelioration of cell loss by BDNF (p < 0.001). Moreover, BDNF gene delivery improved synaptophysin immunoreactivity in the entorhinal cortex and, through anterograde BDNF transport, in the hippocampus (p < 0.01). Notably, BDNF did not affect amyloid plaque numbers, indicating that direct amyloid reduction is not necessary to achieve significant neuroprotective benefits in mutant amyloid models of Alzheimer's disease.
Department of Neurosciences-0626, University of California, San Diego, La Jolla, California 92093, and Veterans Affairs Medical Center, San Diego, California 92161.
Alan H
AH
Nagahara
Michael
M
Mateling
Imre
I
Kovacs
Ling
L
Wang
Simone
S
Eggert
Edward
E
Rockenstein
Edward H
EH
Koo
Eliezer
E
Masliah
Mark H
MH
Tuszynski
D000544:Alzheimer Disease / Q000235:genetics / Q000628:therapy; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism; D016923:Cell Death / Q000235:genetics; D003214:Conditioning, Classical; D018728:Entorhinal Cortex / Q000473:pathology*; D005239:Fear; D015316:Genetic Therapy; D006624:Hippocampus / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D058225:Plaque, Amyloid / Q000378:metabolism; D021381:Protein Transport; D016708:Synaptophysin / Q000235:genetics / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D019208:Brain-Derived Neurotrophic Factor; D016708:Synaptophysin