Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo.
The amyloid beta peptide aggregates into amyloid plaques at presymptomatic stages of Alzheimer's disease, but the temporal relationship between plaque formation and neuronal dysfunction is poorly understood. Here we demonstrate that the connectivity of the peripheral olfactory neural circuit is perturbed in mice overexpressing human APPsw (Swedish mutation) before the onset of plaques. Expression of human APPsw exclusively in olfactory sensory neurons also perturbs connectivity with associated reductions in odour-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons project correctly in mice overexpressing wild-type human amyloid precursor protein throughout the brain and in mice overexpressing M671V human APP, a missense mutation that reduces amyloid beta production, exclusively in olfactory sensory neurons. Furthermore, expression of Aβ40 or Aβ42 solely in the olfactory epithelium disrupts the olfactory sensory neuron axon targeting. Our data indicate that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.
Department of Neurology, MassGeneral Institute of Neurodegenerative Disease, Harvard Medical School, Boston, Massachusetts                 02129, USA.
Luxiang
L
Cao
Benjamin R
BR
Schrank
Steve
S
Rodriguez
Eric G
EG
Benz
Thomas W
TW
Moulia
Gregory T
GT
Rickenbacher
Alexis C
AC
Gomez
Yona
Y
Levites
Sarah R
SR
Edwards
Todd E
TE
Golde
Bradley T
BT
Hyman
Gilad
G
Barnea
Mark W
MW
Albers
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009431:Neural Conduction; D055696:Olfactory Perception; D058225:Plaque, Amyloid / Q000378:metabolism; D011984:Sensory Receptor Cells / Q000502:physiology*
D016229:Amyloid beta-Peptides