Lysosomal LAMP1 immunoreactivity exists in both diffuse and neuritic amyloid plaques in the human hippocampus

Abstract

Lysosomal vesicles around neuritic plaques are thought to drive Alzheimer's disease by providing ideal microenvironments for generation of amyloid-β. Although lysosomal vesicles are present at every amyloid plaque in mouse models of Alzheimer's disease, the number of amyloid plaques that contain lysosomal vesicles in the human brain remains unknown. This study aimed to quantify lysosomal vesicles at amyloid plaques in the human hippocampus. Lysosome-associated membrane protein 1 (LAMP1)-positive vesicles accumulated in both diffuse (Aβ42-positive/AT8-negative) and neuritic (Aβ42-positive/AT8-positive) plaques in all regions were analysed. In contrast to mouse models of Alzheimer's disease, however, not all amyloid plaques accumulated LAMP1-positive lysosomal vesicles. Even at neuritic plaques, LAMP1 immunoreactivity was more abundant than phospho-tau (AT8). Further, lysosomal vesicles colocalised weakly with phospho-tau such that accumulation of lysosomal vesicles and phospho-tau appeared to be spatially distinct events that occurred within dystrophic neurites. This quantitative study shows that diffuse plaques, as well as neuritic plaques, contain LAMP1 immunoreactivity in the human hippocampus.

Microglia use TAM receptors to detect and engulf amyloid β plaques

“…Amyloid plaques are typically surrounded by a halo of dystrophic neuronal membranes 37 . This halo is shaped by microglial phagocytic activity 37 , and is marked by the expression of several proteins, including the autophagic and endo-lysosomal vesicular marker LAMP1 38 (examples in Fig. 5c ).…”

TMEM59 Haploinsufficiency Ameliorates the Pathology and Cognitive Impairment in the 5xFAD Mouse Model of Alzheimer’s Disease

“…The formation of dystrophic neurites is also one pathological trait in AD (Holcomb et al, 1998;Guo et al, 2020). Many previous studies have demonstrated that LAMP1, a lysosomal marker for endo-lysosomal and autophagic vesicles, is enriched in dystrophic neurites and accumulates around Aβ plaques in AD mouse models (Condello et al, 2011;Gowrishankar et al, 2015;Yuan et al, 2016) as well as in AD patients (Terry et al, 1964;Barrachina et al, 2006;Hassiotis et al, 2018). Therefore, LAMP1 staining has been used as a marker for dystrophic neurites.…”

Hijacking Endocytosis and Autophagy in Extracellular Vesicle Communication: Where the Inside Meets the Outside

“…This is further supported by animal models of late-onset neurodegenerative disorders, which display a progressive accumulation of autophagic organelles and protein aggregates (Spencer et al, 2009;Decressac et al, 2013;Valionyte et al, 2020). Furthermore, nanoscale analysis performed on postmortem brain tissue slice of patients affected by AD and PD showed that beta-amyloid and alpha-synuclein inclusions were enriched in lipid membranes and organelles structurally resembling lysosomes and in part immune-reactive for lysosomal markers (Nixon et al, 2005;Hassiotis et al, 2018;Shahmoradian et al, 2019). Similar observations were made with the identification of intralysosomal prion inclusions in neurons of sporadic Creutzfeldt-Jakob disease brains (Kovács et al, 2007).…”