INTRODUCTION: Cell biological and genetic evidence implicates failures in degrading aggregating proteins, such as tau and TDP-43, through autophagy or lysosomal pathways in the pathogenesis of Frontotemporal Lobar degeneration (FTLD).
METHODS: We investigated changes in degradative pathways in 60 patients with different pathological or genetic forms of FTLD employing immunohistochemistry for marker proteins such as Lysosomal Associated Membrane Proteins 1 (LAMP-1) and 2 (LAMP-2), Cathepsin D (CTSD) and microtubule-associated protein 1 light chain 3 alpha (LC3A). Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining in neurones of dentate gyrus (DG) and CA4 region of hippocampus, and temporal cortex (Tcx).
RESULTS: Lower levels of neuronal LAMP-1 immunostaining were present in DG and Tcx in FTLD-tau compared to FTLD-TDP. There was less LAMP-1 immunostaining in FTLD-tau with MAPT mutations, and FTLD-tau with Pick bodies, compared to FTLD-TDP types A and B, and less LAMP-1 immunostaining in FTLD-TDP type C than in FTLD-TDP types A and B. There was greater LAMP-1 immunostaining in GRN mutation which may reflect the underlying type A histology rather than mutation. There were no differences in neuronal LAMP-2, CTSD, EEA-1 or LC3A immunostaining between any of the 5 FTLD histological or 4 genetic groups, nor between FTLD-TDP and FTLD-tau.
CONCLUSIONS: The underlying pathological mechanism in FTLD-tau may lie with a relative deficiency of lysosomes, or defective vesicular transport, whereas the failure to clear TDP-43 aggregates may lie with lysosomal dysfunction rather than a lack of available lysosomes or degradative enzymes. This article is protected by copyright. All rights reserved.