Axonopathy in an APP/PS1 transgenic mouse model of Alzheimer's disease

Acta Neuropathologica
O WirthsT A Bayer

Abstract

While axonopathy is a prominent feature in a variety of neurodegenerative diseases, it has been largely neglected in Alzheimer's disease (AD), despite the observation of frequent motoric deficits in AD patients. In the present report we used transgenic mice overexpressing human mutant beta-amyloid precursor protein (APP(751SL)) and presenilin-1 (PS1(M146L)) that exhibit elevated intraneuronal Abeta42 levels. We observed abundant age-dependent axonopathy in the spinal cord: axons immunopositive for ubiquitin in the dorsal column; axonal swellings (spheroids) which accumulated APP, neurofilament, and ubiquitin; as well as myelin ovoid structures, which serve as markers for nerve fiber degeneration in both white and gray matter. Both descending and ascending axonal tracts in white matter were affected. Neuritic plaques also developed in an age-dependent manner starting in the cervical region. Furthermore, early intraneuronal Abeta was detected in some but not all motor neurons before plaque formation. In the present APP/PS1 transgenic mouse model we could show for the first time that elevated intracellular Abeta levels lead to an axonopathy characterized by the formation of axonal spheroids and myelin ovoids. The same pathological...Continue Reading

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