EXPRESSION OF THE DUAL LEUCINE ZIPPER KINASE IN DYSTROPHIC NEURITES AND AXONAL BEADING DURING PATHOLOGY PROGRESSION IN ALZHEIMER’S DISEASE

Abstract

The Dual Leucine Zipper Kinase (DLK) is an evolutionary conserverd Ser/Thr Kinase and main regulator of Wallerian degeneration, which is characterized by a “dying back mechanism” of axonal processes prior to neuronal cell death. Recently, DLK emerged as an attractive drug target for AD as genetic loss of DLK confers neuroprotection in both an amyloid and a taupathy mouse models. However, DLK expression in the brain and subcellular localization during the pathology process in AD has not been reported. We used immunofluorescence staining and immunohistochemistry to characterize DLK exporession in the brain from AD mouse models and from patients affected by AD at different Braak stages. In all preclinical models examined, DLK is redistributed in axonal beading and dystrophic neurites near amyloid deposits. A similar phenotype was observed in human AD, especially at late Braak stages. In addition, phosphorylation of JNK is DLK-dependent in in dystrophic neurites suggesting that DLK may be locally activated in these pathological presynaptic structures. We propose that DLK acts as a axonal sensor of neuronal stress induced by amyloid and tau pathology in AD and might play a critical role in triggering Wallerian degeneration in AD.