Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease.
Profound neuronal dysfunction in the entorhinal cortex contributes to early loss of short-term memory in Alzheimer's disease. Here we show broad neuroprotective effects of entorhinal brain-derived neurotrophic factor (BDNF) administration in several animal models of Alzheimer's disease, with extension of therapeutic benefits into the degenerating hippocampus. In amyloid-transgenic mice, BDNF gene delivery, when administered after disease onset, reverses synapse loss, partially normalizes aberrant gene expression, improves cell signaling and restores learning and memory. These outcomes occur independently of effects on amyloid plaque load. In aged rats, BDNF infusion reverses cognitive decline, improves age-related perturbations in gene expression and restores cell signaling. In adult rats and primates, BDNF prevents lesion-induced death of entorhinal cortical neurons. In aged primates, BDNF reverses neuronal atrophy and ameliorates age-related cognitive impairment. Collectively, these findings indicate that BDNF exerts substantial protective effects on crucial neuronal circuitry involved in Alzheimer's disease, acting through amyloid-independent mechanisms. BDNF therapeutic delivery merits exploration as a potential therapy for Alzheimer's disease.
Nagahara
Alan H
AH
Department of Neurosciences-0626, 9500 Gilman Drive, University of California-San Diego, La Jolla, California 92093, USA.
Merrill
David A
DA
Coppola
Giovanni
G
Tsukada
Shingo
S
Schroeder
Brock E
BE
Shaked
Gideon M
GM
Wang
Ling
L
Blesch
Armin
A
Kim
Albert
A
Conner
James M
JM
Rockenstein
Edward
E
Chao
Moses V
MV
Koo
Edward H
EH
Geschwind
Daniel
D
Masliah
Eliezer
E
Chiba
Andrea A
AA
Tuszynski
Mark H
MH
D000544:Alzheimer Disease / Q000188:drug therapy*; D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000627:therapeutic use*; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011323:Primates
D019208:Brain-Derived Neurotrophic Factor; D018696:Neuroprotective Agents