Amyloid plaques are formed from beta amyloid peptide aggregates and occur at presymptomatic stages of Alzheimer’s disease. However, the temporal relationship between plaque formation and neuronal dysfunction is not yet well understood. To study this, different variants of human amyloid precursor protein (APP) or Aβ40 or Aβ42 were expressed in mice.

The authors of this paper demonstrate that neuronal dysfunction may occur before the appearance of plaques in mice overexpressing human APPsw (APP Swedish mutation). APPsw has a mutation at codons 670/671 which leads to enhanced cleavage at the -secretase scissile bond and increased Aβ formation. In this study, overexpression of human APPsw perturbed the connectivity of the peripheral olfactory neural circuit.  Expression of human APPsw exclusively in olfactory sensory neurons also perturbed connectivity and was associated with reductions in odor-evoked gene expression and olfactory acuity. By contrast, olfactory sensory neuron axons projected 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 disrupted the olfactory sensory neuron axon targeting. The authors suggest that altering the structural connectivity and function of highly plastic neural circuits is one of the pleiotropic actions of soluble human amyloid beta.

Cao L, Schrank BR, Rodriguez S, Benz EG, Moulia TW, Rickenbacher GT, Gomez AC, Levites Y, Edwards SR, Golde TE, Hyman BT, Barnea G, Albers MW: Aβ alters the connectivity of olfactory neurons in the absence of amyloid plaques in vivo. Nature Communications 3, article number: 1009 [doi:10.1038/ncomms2013,  published August 21, 2012].

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