Li X, Tsolis KC, Koper MJ, Ronisz A, Ospitalieri S, von Arnim CA, Vandenberghe R, Tousseyn T, Scheuerle A, Economou A, Carpentier S, Otto M, Thal DR. Sequence of proteome profiles in preclinical and symptomatic Alzheimer's disease. Alzheimers Dement. 2021 Jun;17(6):946-958. Epub 2021 Apr 19 PubMed.

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  1. The study, led by Dietmar Thal, is fascinating since it does an excellent pathological characterization of the postmortem tissue, focusing on the earliest changes and disease progression.

    I am pleased to see that proteins functioning in the secretory and endocytic pathway changed in the preclinical phase. This proteomic analysis provides one more piece of the puzzle that indicates that endosomal/secretory defects are an essential mechanism early in AD. Moreover, it supports that synaptic dysfunction, namely of the synaptic vesicle cycle, is an early target in AD.

    I was a bit surprised that only four proteins changed from control to pathological but not yet demented frontal cortex. I am also left wondering about the patient's genotypes. Maybe for futures studies, the presence of genes related to AD could be correlated with proteome changes.

    View all comments by Claudia Almeida

  2. Lee et al. describe a creative approach to the proteomic analysis of AD brain tissue by tracking not only changing protein levels but also shifts in solubility characteristics of individual proteins and their compartmentalization in cells. Although the brain sample is cell heterogeneous, there is reason to believe that some of these shifts may be taking place in multiple cell types given the conserved functions of vesicular trafficking processes implicated by the authors. The endocytic pathway highlighted by the authors is one such pathway, which is strongly linked to genetic risk for AD.

    Another particularly interesting group of differentially expressed proteins (DEPs) not highlighted in the report is related to autophagy. Protein changes implying autophagy induction and autophagosome biogenesis include RAB1a and CLUS elevations and decreasing UCHL1 and PLEC levels. Even some of the proteins characterized as a “secretory pathway” cluster encompass Golgi functions that are relevant to lysosome functioning in the autophagy pathway (Lie et al., 2021). The autophagy response suggested here is consistent with our evidence in single population analyses of CA1 hippocampal neurons that autophagy is progressively induced starting at early AD stages, even though flux through the pathway ultimately fails as lysosomal function declines (Bordi et al., 2016).

    It is interesting to speculate that increased levels of certain DEPs in the “dispersible” brain fraction, which comprises vesicular compartments of the endosomal-lysosomal-autophagy network, could reflect the upregulated sequestration of substrates into autophagic vacuoles as well as into endocytic compartments, which swell due to upregulated endocytosis in AD.

    Curiously, the rises in some abundant cytoskeleton-related proteins that are autophagy substrates (e.g. NFH, tau, vimentin) along with others in the “dispersible” vesicle and fraction-shifting groups may reflect their gradual accumulation as substrates due to the progressive declines of lysosomal efficiency and autophagy flux as AD advances (Bordi et al., 2016). 

    Future studies involving detection of a larger population of brain proteins and higher numbers of DEPs will yield improved definition of the disease-related biological pathways in order to confirm the intriguing leads reported here.

    References:

    Lie PP, Yang DS, Stavrides P, Goulbourne CN, Zheng P, Mohan PS, Cataldo AM, Nixon RA. Post-Golgi carriers, not lysosomes, confer lysosomal properties to pre-degradative organelles in normal and dystrophic axons. Cell Rep. 2021 Apr 27;35(4):109034. PubMed.

    Bordi M, Berg MJ, Mohan PS, Peterhoff CM, Alldred MJ, Che S, Ginsberg SD, Nixon RA. Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy. 2016 Dec;12(12):2467-2483. Epub 2016 Nov 4 PubMed.

    View all comments by Ralph Nixon

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  1. Proteomics Dates Endosomal, Synaptic Changes to Preclinical AD