BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice.
Evidence suggests that beta-amyloid (Abeta) peptide triggers a pathogenic cascade leading to neuronal loss in Alzheimer's disease (AD). However, the causal link between Abeta and neuron death in vivo remains unclear since most animal models fail to recapitulate the dramatic cell loss observed in AD. We have recently developed transgenic mice that overexpress human APP and PS1 with five familial AD mutations (5XFAD mice) and exhibit robust neuron death. Here, we demonstrate that genetic deletion of the beta-secretase (BACE1) not only abrogates Abeta generation and blocks amyloid deposition but also prevents neuron loss found in the cerebral cortex and subiculum, brain regions manifesting the most severe amyloidosis in 5XFAD mice. Importantly, BACE1 gene deletion also rescues memory deficits in 5XFAD mice. Our findings provide strong evidence that Abeta ultimately is responsible for neuron death in AD and validate the therapeutic potential of BACE1-inhibiting approaches for the treatment of AD.
Ohno
Masuo
M
Department of Physiology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611-3008, USA. mohno@nki.rfmh.org
Cole
Sarah L
SL
Yasvoina
Marina
M
Zhao
Jie
J
Citron
Martin
M
Berry
Robert
R
Disterhoft
John F
JF
Vassar
Robert
R
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D005911:Gliosis / Q000235:genetics / Q000473:pathology; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics* / Q000523:psychology*; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology*
D016564:Amyloid beta-Protein Precursor; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human