Simoes S, Neufeld JL, Triana-Baltzer G, Moughadam S, Chen EI, Kothiya M, Qureshi YH, Patel V, Honig LS, Kolb H, Small SA. Tau and other proteins found in Alzheimer's disease spinal fluid are linked to retromer-mediated endosomal traffic in mice and humans. Sci Transl Med. 2020 Nov 25;12(571) PubMed.

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  1. The authors report exciting new findings showing that two BACE1 substrates—the transmembrane proteins APLP1 and CHL1—are found, along with mid-domain tau, in the CSF of a mouse model of endosomal trafficking as well as in human AD versus control patient CSF.

    The results build on previous findings on endosomal trafficking impairments in AD. To my mind, the most important contribution is the demonstration of associations between tau and BACE1 in endosomal trafficking, as well as the development and application of SIMOA assays to readily measure APLP1 and CHL1 levels in human and mouse CSF. 

    BACE1 acts on APP to initiate Aβ production and plaque formation, which, in turn, causes BACE1 accumulation in dystrophic neurites. Increased APLP1 and CHL1 could therefore be indicate plaque formation in AD. Elevation of total and phosphorylated tau in the same individuals, and their strong correlations with the BACE1 substrate levels, suggests that tau pathophysiological changes begin very early in the AD continuum, alongside Aβ abnormalities. This is in line with recent studies showing that, contrary to the commonly held theory that tau pathology begins several years after plaque pathology, specific p-tau variants begin to occur almost concurrently with initial Aβ abnormalities (Janelidze et al., 2020; Suárez-Calvet and Karikari et al., 2020; Karikari et al., 2020). 

    This close association between tau, Aβ, and BACE1 activity has been shown previously. Tau deletion in mouse models reduced plaque formation, plaque-associated BACE1 accumulation and APP accumulation around plaques (Peters et al., 2019). Pharmacological inhibition of BACE1 activity in APP transgenic mice reduced CSF tau and brain Aβ levels, suggesting that CSF tau can be used as an outcome measure for BACE1 inhibitor function (Schelle et al., 2016). 

    It will be interesting to compare the associations between different p-tau biomarkers (for example, p-tau181, p-tau217, p-tau231) with these BACE1-associated proteins in mouse models and humans. 

    References:

    Janelidze S, Stomrud E, Smith R, Palmqvist S, Mattsson N, Airey DC, Proctor NK, Chai X, Shcherbinin S, Sims JR, Triana-Baltzer G, Theunis C, Slemmon R, Mercken M, Kolb H, Dage JL, Hansson O. Cerebrospinal fluid p-tau217 performs better than p-tau181 as a biomarker of Alzheimer's disease. Nat Commun. 2020 Apr 3;11(1):1683. PubMed.

    Suárez-Calvet M, Karikari TK, Ashton NJ, Lantero Rodríguez J, Milà-Alomà M, Gispert JD, Salvadó G, Minguillon C, Fauria K, Shekari M, Grau-Rivera O, Arenaza-Urquijo EM, Sala-Vila A, Sánchez-Benavides G, González-de-Echávarri JM, Kollmorgen G, Stoops E, Vanmechelen E, Zetterberg H, Blennow K, Molinuevo JL, ALFA Study. Novel tau biomarkers phosphorylated at T181, T217 or T231 rise in the initial stages of the preclinical Alzheimer's continuum when only subtle changes in Aβ pathology are detected. EMBO Mol Med. 2020 Dec 7;12(12):e12921. Epub 2020 Nov 10 PubMed.

    Karikari TK, Emeršič A, Vrillon A, Lantero-Rodriguez J, Ashton NJ, Kramberger MG, Dumurgier J, Hourregue C, Čučnik S, Brinkmalm G, Rot U, Zetterberg H, Paquet C, Blennow K. Head-to-head comparison of clinical performance of CSF phospho-tau T181 and T217 biomarkers for Alzheimer's disease diagnosis. Alzheimers Dement. 2021 May;17(5):755-767. Epub 2020 Nov 30 PubMed. Correction.

    Peters F, Salihoglu H, Pratsch K, Herzog E, Pigoni M, Sgobio C, Lichtenthaler SF, Neumann U, Herms J. Tau deletion reduces plaque-associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer's disease. EMBO J. 2019 Dec 2;38(23):e102345. Epub 2019 Nov 7 PubMed.

    Schelle J, Häsler LM, Göpfert JC, Joos TO, Vanderstichele H, Stoops E, Mandelkow EM, Neumann U, Shimshek DR, Staufenbiel M, Jucker M, Kaeser SA. Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. 2016 Oct 14; PubMed.

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