Im E, Jiang Y, Stavrides PH, Darji S, Erdjument-Bromage H, Neubert TA, Choi JY, Wegiel J, Lee JH, Nixon RA. Lysosomal dysfunction in Down syndrome and Alzheimer mouse models is caused by v-ATPase inhibition by Tyr682-phosphorylated APP βCTF. Sci Adv. 2023 Jul 28;9(30):eadg1925. Epub 2023 Jul 26 PubMed.

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  1. This thorough study pinpoints a mechanism describing lysosomal dysfunction in AD. In both DS and FAD mouse models, the Nixon group show that a phosphorylated form of β-CTF of APP directly interacts with and inhibits a v-ATPase subunit that is involved in proper lysosomal acidification.

    Lysosomal dysfunction is an early and universal hallmark of AD. By elucidating this mechanism, this paper readily identifies new therapeutic targets: phosphorylation sites on APP β -CTF and molecules to improve lysosomal acidification. It will be interesting for future studies to determine the extent of this dysfunction in the various cell types of the CNS.

    View all comments by Jessica Young

  2. This study is elegant and intriguing. It supports a crucial role of increased phosphorylation levels of the APP Tyr682 residue in the neurons of patients with AD and DS. The study provides a mechanism through which this increased phosphorylation leads to dysfunctional and defective lysosomes by preventing correct lysosomal v-ATPase assembly, compromising its activity.

    Furthermore, it suggests an interaction between lysosomal v-ATPase and the APP/YENPTY motif via the Tyr682 residue, implying that targeting v-ATPase, specifically its subunit V0a1, may have clinical implications, particularly in individuals with elevated phosphorylation levels of the Try682 residue.

    Further research is necessary to explore how changes in APP Tyr682 phosphorylation affect its adaptor interactions in patients with AD throughout various stages of the disease in order to predict clinical outcomes and progression.

    It would be interesting to ascertain whether the same interaction between v-ATPAse and the APP/YENPTY motif also occurs in blood mononuclear cells from patients. This is relevant because we have previously reported that APP Tyr682 phosphorylation levels are increased in the blood mononuclear cells of patients with AD (Ferretti et al., 2023), and suggested that the Tyr682 phosphorylation might have diagnostic and therapeutic implications, using inhibitors of Fyn tyrosine kinase (Iannuzzi et al., 2020, 2021). Translation of these findings to peripheral blood cells could pave the way for new diagnostic strategies and allow the design of personalized therapeutic approaches for patients with increased APP Tyr682 phosphorylation.

    References:

    Ferretti G, Serafini S, Angiolillo A, Monterosso P, Di Costanzo A, Matrone C. Advances in peripheral blood biomarkers of patients with Alzheimer's disease: Moving closer to personalized therapies. Biomed Pharmacother. 2023 Sep;165:115094. Epub 2023 Jun 29 PubMed.

    Iannuzzi F, Sirabella R, Canu N, Maier TJ, Annunziato L, Matrone C. Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer's Disease Patients. Cells. 2020 Jul 30;9(8) PubMed. Correction.

    Iannuzzi F, Frisardi V, Annunziato L, Matrone C. Might Fibroblasts from Patients with Alzheimer's Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue. Brain Sci. 2021 Jan 14;11(1) PubMed. Correction.

    View all comments by Carmela Matrone

  3. This study expands the extent to which lysosome dysfunction—particularly through interference of the vATPase proton pump—is implicated as an upstream pathogenic, cellular mechanism in neurological conditions such as AD and in DS, which share many proteinopathy features.

    The role of specific APP fragments in driving lysosome dysfunction is particularly notable in light of Randy Nixon's previous work demonstrating the role of mutant PS1 similarly interfering with proton pump assembly and lysosome functions. Thus, it appears that these two protein products of fAD-causing genes share a common pathological endpoint resulting in aberrant protein and cellular debris accumulation. 

    The possible contribution of APP to tonic lysosome regulation is also a novel finding with far broader implications, as several neurological conditions, such as brain injury, result in increased APP generation. Notably, TBI and AD also share many histopathological phenotypes. Revealing the central role of lysosome dysfunction across many brain conditions will be of great interest and clinical relevance. 

    View all comments by Grace Stutzmann

  4. This is an exciting study implicating the BACE1-generated APP C-terminal fragment as a key player in lysosomal dysfunction in Down’s syndrome fibroblasts and animal models. This work has a major translational implication for the use of BACE inhibitors. These inhibitors not only have two beneficial effects, namely reduced Aβ generation and increased production of the neuroprotective sAPPα, but also a third beneficial effect, namely lowered abundance of the BACE1-generated APP C-terminal fragment.

    Thus, BACE inhibitors may correct lysosomal dysfunctions, both in AD and in Down’s syndrome. Yet, at high doses, BACE inhibitors also have an undesired side effect and induce a mild cognitive worsening in patients. A dose reduction to clearly less than 50 percent BACE inhibition is assumed to prevent the cognitive worsening and is considered for forthcoming clinical trials. Future work needs to determine how strongly such a reduced dose of a BACE inhibitor may correct lysosomal dysfunctions in vivo.

    View all comments by Stefan Lichtenthaler

  5. This work is thrilling and interesting as the authors continue to report deficits of the endo-lysosomal system in aging and neurodegeneration. In both Down's and AD brains, the phosphorylated APP-β-CTF fragment selectively binds to the V0a1 subunit of the v-ATPase and inhibits lysosomal acidification and subsequent degradative activity, which eventually leads to abnormal protein accumulation and neuronal death. This paper and their previously published work (Lee et al., 2022), show a direct link of maladaptive APP fragments to lysosomal deficits, furthering the hypothesis that disrupted intracellular organelle function is an early mechanism for Alzheimer’s pathogenesis.

    Early calcium dysregulation can also feed into this process by increasing BACE1 activity and altering phosphotase/kinase activity, both pathways that encourage phosphorylated-APP-BCTF production (Stutzmann, 2007; Chami and Checler, 2012). Additionally, calcium dysregulation via ryanodine receptors was shown to disrupt lysosomal acidfication and lead to increased hyperphosphoryated tau accumulation in autolysosomes (Mustaly-Kalimi et al., 2022). 

    Hyperphosphorylated protein targets, hence, are being sequestered into these compartments and disrupting lysosomal degradative activity; therefore targeting mechanisms that reduce maladaptive protein accumulation and increase lysosomal acidification can be an early, beneficial therapeutic for Alzheimer’s disease. This study, and others, have shown that reducing APP levels, reacidfication of lysosomes, and decreasing calcium dysregulation can improve lysosomal function in AD (Lee et al., 2015; Mustaly-Kalimi et al., 2022). 

    References:

    Chami L, Checler F. BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer's disease. Mol Neurodegener. 2012;7:52. PubMed.

    Lee JH, McBrayer MK, Wolfe DM, Haslett LJ, Kumar A, Sato Y, Lie PP, Mohan P, Coffey EE, Kompella U, Mitchell CH, Lloyd-Evans E, Nixon RA. Presenilin 1 Maintains Lysosomal Ca(2+) Homeostasis via TRPML1 by Regulating vATPase-Mediated Lysosome Acidification. Cell Rep. 2015 Sep 1;12(9):1430-44. Epub 2015 Aug 20 PubMed.

    Lee JH, Yang DS, Goulbourne CN, Im E, Stavrides P, Pensalfini A, Chan H, Bouchet-Marquis C, Bleiwas C, Berg MJ, Huo C, Peddy J, Pawlik M, Levy E, Rao M, Staufenbiel M, Nixon RA. Faulty autolysosome acidification in Alzheimer's disease mouse models induces autophagic build-up of Aβ in neurons, yielding senile plaques. Nat Neurosci. 2022 Jun;25(6):688-701. Epub 2022 Jun 2 PubMed.

    Mustaly-Kalimi S, Gallegos W, Marr RA, Gilman-Sachs A, Peterson DA, Sekler I, Stutzmann GE. Protein mishandling and impaired lysosomal proteolysis generated through calcium dysregulation in Alzheimer's disease. Proc Natl Acad Sci U S A. 2022 Dec 6;119(49):e2211999119. Epub 2022 Nov 28 PubMed.

    Stutzmann GE. The pathogenesis of Alzheimers disease is it a lifelong "calciumopathy"?. Neuroscientist. 2007 Oct;13(5):546-59. PubMed.

    View all comments by Sarah Mustaly

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News

  1. Too Basic: APP β-CTF's YENTPY Motif Binds Proton Pump, Thwarts Lysosomes

Mutations

  1. Trisomy 21