Increased Human Wildtype Tau Attenuates Axonal Transport Deficits Caused by Loss of APP in Mouse Models

Karen D.B. Smith1, Erica Peethumnongsin2, Han Lin1, Hui Zheng2,3,4,6 and Robia G. Pautler1,4,5,61Department of Molecular Physiology and Biophysics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. 2Interdepartmental Program in Cell and Molecular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. 3Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. 4Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. 5Department of Radiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. 6Department of Neuroscience, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 USA. Abstract Amyloid precursor protein (APP) is implicated in axonal elongation, synaptic plasticity, and axonal transport. However, the role of APP on axonal transport in conjunction with the microtubule associated protein tau continues to be debated. Here we measured in vivo axonal transport in APP knockout mice with Manganese Enhanced MRI (MEMRI) to determine whether APP is necessary for maintaining normal axonal transport. We also tested how overexpression and mutations of tau affect axonal transport in the presence or absence of APP. In vivo axonal transport reduced significantly in the absence of functional APP. Overexpression of human wildtype tau maintained normal axonal transport and resulted in a transient compensation of axonal transport deficits in the absence of APP. Mutant R406Wtau in combination with the absence of APP compounded axonal transport deficits and these deficits persisted with age. These results indicate that APP is necessary for axonal transport, and overexpression of human wildtype tau can compensate for the absence of APP at an early age.