Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

Abstract

Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…In line with previous studies (30,55,56), we did observe some heterogeneity among axonal lysosomes. For example, in the distal axon, lysosomes were less mobile, and some were less acidic (Fig.…”

Local Cues Establish and Maintain Region-Specific Phenotypes of Basal Ganglia Microglia

“…We found greater than 2-fold variation in BG microglial lysosome content, supporting the conclusion that microglial functional status varies across BG nuclei. The ability of individual lysosomes to process substrates and influence diverse aspects of cell function depends on abundance of lysosomal membrane proteins and matrix proteases, which can vary across cell types and subcellular locations (Brix, 2005; Gowrishankar et al, 2015; Johnson et al, 2016). Analysis of additional lysosomal membrane and matrix proteins will be needed to determine whether regional differences in BG microglial lysosome content are accompanied by differences in lysosome “maturational state.”…”

Par3 and aPKC regulate BACE1 endosome-to-TGN trafficking through PACS1

“…This will increase the chance for BACE1 to converge with APP and facilitates Aβ generation, as Aβ has been reported to be generated in early endosomes (Kinoshita et al, 2003; Rajendran et al, 2006; Udayar et al, 2013), recycling endosomes (Das et al, 2013; Das et al, 2016), as well as late endosomes/multi-vesicular bodies and lysosomes (Edgar et al, 2015; Sannerud et al, 2016; Tam et al, 2014; Tang et al, 2015). Lysosomal defects that are wide-spread in the AD brain likely exacerbate the BACE1 and Aβ accumulations in these degradative organelles (Gowrishankar et al, 2015) or in late endocytic organelles destined for fusion with lysosomes (Takahashi et al, 2002; Ye and Cai, 2014). Intriguingly, Aβ40 is also generated in the TGN after retrograde trafficking from the endosomes in non-neuronal cells; however, the convergence with BACE1 is believed to occur in the endosomes (Choy et al, 2012).…”