Neuropathological characterization of Lemur tyrosine kinase 2 (LMTK2) in Alzheimer’s disease and neocortical Lewy body disease

Abstract

Alzheimer’s disease (AD) and neocortical Lewy body disease (LBD) are the most common neurodegenerative dementias, with no available curative treatment. Elucidating pathomechanism and identifying novel therapeutic targets are of paramount importance. Lemur tyrosine kinase 2 (LMTK2) is involved in several physiological and pathological cellular processes. Herewith a neuropathological characterization is presented in AD and neocortical LBD samples using chromogenic and fluorescent LMTK2 immunohistochemistry on post-mortem brain tissues and compared them to age-matched controls (CNTs). LMTK2 immunopositivity was limited to the neuronal cytoplasm. Neurons, including tau-positive tangle-bearing ones, showed decreased chromogenic and immunofluorescent labelling in AD in every cortical layer compared to CNT and neocortical LBD. Digital image analysis was performed to measure the average immunopositivity of groups. Mean grey values were calculated for each group after measuring the grey scale LMTK2 signal intensity of each individual neuron. There was significant difference between the mean grey values of CNT vs. AD and neocortical LBD vs. AD. The moderate decrease in neocortical LBD suggests the effect of coexisting AD pathology. We provide neuropathological evidence on decreased neuronal LMTK2 immunolabelling in AD, with implications for pathogenesis.

Lemur Tyrosine Kinase 2 (LMTK2) Level Inversely Correlates with Phospho-Tau in Neuropathological Stages of Alzheimer’s Disease

“…In accordance with our findings, recent studies have shown decreased LMTK2 level in AD [12,13,19]. A genome-wide gene expression analysis detected reduced LMTK2 expression in the cortex of transgenic Tau P301L mice [19].…”

“…Alterations of LMTK2 level may contribute to neurodegeneration by disrupted axonal transport, enhanced apoptosis and tau hyperphosphorylation [11]. We previously described decreased LMTK2 level in human postmortem AD brains compared to age-matched controls [13]. Our immunohistochemical (IHC) results were in accordance with other human and animal model studies [12,19].…”

“…However, the investigated region(s) of the frontal cortex were not specified, thus direct comparison with our results is not possible. In our previous paper we reported significantly decreased immunolabelling in the middle frontal gyrus of patients with Braak stage VI pathology compared to age-matched controls and neocortical Lewy body disease (LBD) cases [13]. Because LBD-specific Lewy body-bearing neurons showed strong LMTK2 immunoreaction and Lewy bodies themselves were negative, we hypothesized that the decreased average immunopositivity (compared to controls) was due to coexisting AD-type pathology.…”

“…The applied immunohistochemical procedure was optimized in our previous work [13]. After routine dewaxing, sections were treated in 3% (v/v) H 2 O 2 :methanol solution for 30 min to block endogenous peroxidase enzymes.…”

“…In general, NFT burden inversely correlates with the number of surviving neurons, proposing that neurofibrillary lesions have a key role in degenerative changes and apoptotic cell loss in AD [10]. The latest studies suggest that there is a link between the expression/activity of recently described lemur tyrosine kinase 2 (LMTK2) protein and tau hyperphosphorylation [11][12][13]. Despite its name, LMTK2 is a member of a membrane-anchored serine/threonine-specific protein kinase family [14][15][16].…”