Lysosomes, autophagosomes and Alzheimer pathology in dementia with Lewy body disease

Abstract

A failure of protein degradation may underpin Lewy body disease (LBD) where α-synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α-synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP-1 and LAMP-2), cathepsin D (CTSD)) and autophagosomal (microtubule-associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi-quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP-1, LAMP-2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP-1 in patients with GBA1 mutations compared to those without. Loss of LAMP-1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP-1 and LAMP-2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid-β. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.

Parallels between retinal and brain pathology and response to immunotherapy in old, late‐stage Alzheimer's disease mouse models

“…Consistent with previous results, the brain displayed a substantial increase in magnitude changes as compared to the retina (Koronyo et al, 2017; Koronyo‐Hamaoui et al, 2011). Finally, the lysosomal‐associated membrane protein 1/2 (LAMP1/2) molecules have also been implicated in the degradation of Aβ fibrils (Barrachina et al, 2006; Gurney et al, 2018) and were found to be up‐regulated in brain and retinal tissues from old ADtg mice. In response to GA immunomodulation, we revealed a preferential down‐regulation of LAMP1 in the brain and LAMP2 in the retina.…”

Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson’s disease brains with Lewy body pathology

“…Furthermore, a number of studies have proposed that basal levels of autophagy are important for the clearance of α-synuclein, thus limiting intracellular oligomerization and formation of aggregates ( Vogiatzi et al, 2008 ). Interestingly, studies on autophagic markers in the context of neurodegenerative disease namely, Dementia with Lewy bodies (DLB) has shown some alterations compared to controls ( Gurney, 2018 , Higashi et al, 2011 ).…”

Targeting of Lysosomal Pathway Genes for Parkinson's Disease Modification: Insights From Cellular and Animal Models

“…In addition to the evidence from genetics, the involvement of lysosomal dysfunction in PD has been implicated from pathological and biochemical studies using postmortem disease samples. The reduction in the immunoreactivity of lysosomal markers, such as LAMP1 and cathepsin D, was detected in PD and Lewy body disease ( 22 , 23 ), and lysosomal breakdown, autophagosomal accumulation and the colocalization of autophagosomal markers with Lewy bodies were also detected in PD brains ( 24 ). Cathepsin D immunoreactivity has been shown to colocalize with α-synuclein pre-aggregates in nigral neurons in PD ( 25 ).…”