Neurodegenerative disorders are frequent, incurable diseases characterised by abnormal protein accumulation and progressive neuronal loss. Despite their growing prevalence, the underlying pathomechanism remains unclear. Lemur tyrosine kinase 2 (LMTK2) is a member of a transmembrane serine/threonine-protein kinase family. Although it was described more than a decade ago, our knowledge on LMTK2’s biological functions is still insufficient. Recent evidence has suggested that LMTK2 is implicated in neurodegeneration. After reviewing the literature, we identified three LMTK2-mediated mechanisms which may contribute to neurodegenerative processes: disrupted axonal transport, tau hyperphosphorylation and enhanced apoptosis. Moreover, LMTK2 gene expression is decreased in an Alzheimer’s disease mouse model. According to these features, LMTK2 might be a promising therapeutic target in near future. However, further investigations are required to clarify the exact biological functions of this unique protein.

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.

Semi-quantitative scoring is a method that is widely used to estimate the quantity of proteins on chromogen-labelled immunohistochemical (IHC) tissue sections. However, it suffers from several disadvantages, including its lack of objectivity and the fact that it is a time-consuming process. Our aim was to test a recently established artificial intelligence (AI)-aided digital image analysis platform, Pathronus, and to compare it to conventional scoring by five observers on chromogenic IHC-stained slides belonging to three experimental groups. Because Pathronus operates on grayscale 0-255 values, we transformed the data to a seven-point scale for use by pathologists and scientists. The accuracy of these methods was evaluated by comparing statistical significance among groups with quantitative fluorescent IHC reference data on subsequent tissue sections. The pairwise inter-rater reliability of the scoring and converted Pathronus data varied from poor to moderate with Cohen’s kappa, and overall agreement was poor within every experimental group using Fleiss’ kappa. Only the original and converted that were obtained from Pathronus original were able to reproduce the statistical significance among the groups that were determined by the reference method. In this study, we present an AI-aided software that can identify cells of interest, differentiate among organelles, protein specific chromogenic labelling, and nuclear counterstaining after an initial training period, providing a feasible and more accurate alternative to semi-quantitative scoring.

Alzheimer’s disease (AD) is the most common neurodegenerative dementia. Mapping the pathomechanism and providing novel therapeutic options have paramount significance. Recent studies have proposed the role of LMTK2 in AD. However, its expression pattern and association with the pathognomonic neurofibrillary tangles (NFTs) in different brain regions and neuropathological stages of AD is not clear. We performed chromogenic (CHR) LMTK2 and fluorescent phospho-tau/LMTK2 double-labelling (FDL) immunohistochemistry (IHC) on 10–10 postmortem middle frontal gyrus (MFG) and anterior hippocampus (aHPC) samples with early and late neuropathological Braak tau stages of AD. MFG in early stage was our ‘endogenous control’ region as it is not affected by NFTs. Semiquantitative CHR-IHC intensity scoring revealed significantly higher (p < 0.001) LMTK2 values in this group compared to NFT-affected regions. FDL-IHC demonstrated LMTK2 predominance in the endogenous control region, while phospho-tau overburden and decreased LMTK2 immunolabelling were detected in NFT-affected groups (aHPC in early and both regions in late stage). Spearman’s correlation coefficient showed strong negative correlation between phospho-tau/LMTK2 signals within each group. According to our results, LMTK2 expression is inversely proportionate to the extent of NFT pathology, and decreased LMTK2 level is not a general feature in AD brain, rather it is characteristic of the NFT-affected regions.

Absztrakt: A Lewy-testes demencia (DLB) és a Parkinson-kórhoz társuló demencia (PDD) számos klinikai, patofiziológiai és morfológiai átfedést mutató neurodegeneratív kórkép. Neuropatológiai szempontból meghatározó a kóros α-szinuklein-aggregátumokat tartalmazó Lewy-testek (LB) jelenléte. DLB-ben nagyszámú LB található a corticalis régiókban, míg PDD-ben elsősorban a subcorticalis területek érintettek. Továbbá, DLB-ben gyakoribb az Alzheimer-kórra (AD) jellegzetes β-amyloid-plakkok és neurofibrillaris kötegek megjelenése. A mai napig vitatott, hogy valóban két külön betegségről vagy egyazon kórkép különböző megnyilvánulásairól van-e szó. A klinikai diagnózis alapja a motoros és a kognitív tünetek megjelenése között eltelt idő: DLB-ben a demencia gyakran a parkinsonizmus előtt jelentkezik, míg PDD-ben a motoros tünetek alakulnak ki korábban. Az egyre pontosabb képalkotó módszerek alapján DLB-ben nagyobb mértékű a corticalis károsodás, a kolinerg deficit, valamint a társuló AD-patológia, mint PDD-ben. Terápiás szempontból a PDD-ben gyakran használt levodopa DLB-ben kevésbé hatékony, sőt növelheti a pszichózis kialakulásának kockázatát, a betegség magtüneteihez tartozó hallucinációk és viselkedési tünetek kezelése pedig a jelentős antipszichotikum-hiperszenzitivitás miatt ütközik nehézségekbe. Összefoglalónkban részletesen tárgyaljuk a kórképek jellegzetességeit a patológia, a radiológia és a klinikai tünetek vonatkozásában, külön figyelmet fordítva az átfedések, valamint a különbségek bemutatására. Orv Hetil. 2020; 161(18): 727–737.