Granulovacuolar degenerating body markers accumulate alongside dysfunctional lysosomes in dystrophic neurites and correlate with cognition in Alzheimer’s disease

Abstract

AbstractBackgroundRecent decades have brought a renaissance in understanding lysosomes and autophagy in neurobiology and neurodegenerative diseases. Neuronal endolysosomes are defective in Alzheimer’s disease (AD), most notably in dystrophic neurites where large numbers of enzymatically inactive lysosomes accumulate, distending axons around β‐amyloid plaques. Granulovacuolar degeneration bodies (GVDBs) are another well‐documented neuropathology associated with AD. These pathological neuronal organelles have two membranes, the outer containing lysosome‐associated membrane proteins suggesting these organelles are a product of frustrated autophagy. To implicate GVDBs in the pathogenesis of AD, we evaluated if GVDBs are present in dystrophic neurites and whether the expression of key GVDB genes are correlated with cognition in AD.MethodsHuman brain with AD and brains from 5xFAD mice were examined with immunohistochemistry and confocal microscopy for the established GVDB marker CK1δ. We also evaluated the recently discovered GVDB marker Golgin a4 and its binding partner ARL1 (implicated in the formation of autophagosomes). Finally, we assessed the association of mRNA levels of these genes in frontal cortex at autopsy with cognition and β‐amyloid pathology in 600 participants in Rush University’s Religious Orders Study and Memory and Aging Project (ROS/MAP).ResultsWe discovered that CK1δ, Golgin 4a and ARL1 accumulate in dystrophic neurites in mouse and human AD brain, partially co‐localizing with the lysosomal enzyme cathepsin B, indicating a portion of the organelles accumulating in dystrophic neurites are likely GVDBs. In ROS/MAP participants, golgin a4 expression inversely correlated with cognitive trajectory (β=‐0.003, p=6.0x10‐4) and β‐amyloid plaque density (β=0.01, p=0.001), while ARL1 directly correlated with longitudinal cognition (β=0.004, p=7.0x10‐4) and β‐amyloid plaque density (β=‐0.01, p=0.027) in a model covarying for age at death, sex, education, APOE genotype, and interval between last visit and death. From these results we constructed a conceptual model of the molecular interaction between dysfunctional lysosomes and dysfunctional autophagic organelles in dystrophic neurites.ConclusionsGVDBs accumulate in dystrophic neurites in AD, indicating the presence of defective autophagic organelles in addition to the known dysfunctional lysosomes. Transcriptomic data demonstrating a correlation of GVDB markers with cognition and β‐amyloid pathology suggests this discovery is likely functionally relevant.