Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

Njavro, Jasenka Rudan; Klotz, Jakob; Dislich, Bastian; Wanngren, Johanna; Shmueli, Merav D.; Herber, Julia; Kuhn, Peer‐Hendrik; Kumar, Rohit; Koeglsperger, Thomas; Conrad, Marcus; Wurst, Wolfgang; Feederle, Regina; Vlachos, Andreas; Michalakis, Stylianos; Jedlicka, Paul; Müller, Stephan; Lichtenthaler, Stefan F.

doi:10.1096/fj.201902347r

Cited by 25 publications

(13 citation statements)

References 92 publications

(226 reference statements)

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“…S5 L and M ). We also found that β-site APP cleaving enzyme 1 –mediated cleavage of the MDGA1 MAM domain did not influence APP binding ( 33 ) ( SI Appendix , Fig. S5 N and O ).…”

Section: Resultsmentioning

confidence: 72%

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Kim

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Balanced synaptic inhibition, controlled by multiple synaptic adhesion proteins, is critical for proper brain function. MDGA1 (meprin, A-5 protein, and receptor protein-tyrosine phosphatase mu [MAM] domain-containing glycosylphosphatidylinositol anchor protein 1) suppresses synaptic inhibition in mammalian neurons, yet the molecular mechanisms underlying MDGA1-mediated negative regulation of GABAergic synapses remain unresolved. Here, we show that the MDGA1 MAM domain directly interacts with the extension domain of amyloid precursor protein (APP). Strikingly, MDGA1-mediated synaptic disinhibition requires the MDGA1 MAM domain and is prominent at distal dendrites of hippocampal CA1 pyramidal neurons. Down-regulation of APP in presynaptic GABAergic interneurons specifically suppressed GABAergic, but not glutamatergic, synaptic transmission strength and inputs onto both the somatic and dendritic compartments of hippocampal CA1 pyramidal neurons. Moreover, APP deletion manifested differential effects in somatostatin- and parvalbumin-positive interneurons in the hippocampal CA1, resulting in distinct alterations in inhibitory synapse numbers, transmission, and excitability. The infusion of MDGA1 MAM protein mimicked postsynaptic MDGA1 gain-of-function phenotypes that involve the presence of presynaptic APP. The overexpression of MDGA1 wild type or MAM, but not MAM-deleted MDGA1, in the hippocampal CA1 impaired novel object-recognition memory in mice. Thus, our results establish unique roles of APP–MDGA1 complexes in hippocampal neural circuits, providing unprecedented insight into trans-synaptic mechanisms underlying differential tuning of neuronal compartment-specific synaptic inhibition.

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“…S5 L and M ). We also found that β-site APP cleaving enzyme 1 –mediated cleavage of the MDGA1 MAM domain did not influence APP binding ( 33 ) ( SI Appendix , Fig. S5 N and O ).…”

Section: Resultsmentioning

confidence: 72%

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Kim

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…Approaches to proteomic investigation of rodent models have typically utilized whole brain homogenate samples or smaller manually dissected areas of localized disease progression (Deng et al, 2018;Njavro et al, 2020;Zheng et al, 2020). A strength of our approach includes the use of the novel rTg-DI rat model of microvascular CAA that largely reflects many of the pathological changes and cognitive deficits observed in humans with CAA and is largely devoid of any parenchymal fibrillar plaque deposition.…”

Section: Discussionmentioning

confidence: 99%

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Schrader

Nostrand

2021

Journal of Neurochemistry

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calcium binding protein A4; S100A6, S100 calcium binding protein A6; SVD, small vessel disease; SWATH-MS, Sequential Window Acquisition of all Theoretical Mass Spectra-MS; Syt2, synaptotagmin-2; TGF-β1, transforming growth factor β1; TNFα, tumor necrosis factor α; TOF-MS, time of flight MS; TPA, total protein approach; UPLC, ultra performance liquid chromatography; VCID, vascular cognitive impairment and dementia; Vim, vimentin; XIC, extracted ion current chromatogram.

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“…Besides APP, more than 60 putative BACE1 substrates have been reported in vitro using proteomic analysis (14)(15)(16)(17). Among them, only a few have been validated to date as BACE1 substrates in vivo, including neuregulin-1, Jagged 1 (Jag1), βsubunits of voltage-gated sodium channel (VGSCβ), amyloid precursor protein-like protein 1 and 2 (APLP1, APLP2), seizure protein 6 (SEZ6), seizure 6-like protein (SEZ6L), L1, cell adhesion molecule L1 like (CHL1), VWFA and cache domain-containing protein 1 (CACHD1), and MAM domaincontaining glycosylphosphatidylinositol anchor protein 1 (MDGA1) (14,(18)(19)(20)(21)(22)(23)(24)(25)(26).…”

mentioning

confidence: 99%

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

Kim

Watanabe

Lomoio

et al. 2021

Journal of Biological Chemistry

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Neural cell adhesion molecules 1 (NCAM1) and 2 (NCAM2) belong to the cell adhesion molecules of the immunoglobulin superfamily and have been shown to regulate formation, maturation, and maintenance of synapses. NCAM1 and NCAM2 undergo proteolysis, but the identity of all the proteases involved and how proteolysis is used to regulate their functions are not known. We report here that NCAM1 and NCAM2 are BACE1 substrates in vivo . NCAM1 and NCAM2 overexpressed in HEK cells were both cleaved by metalloproteinases or BACE1, and NCAM2 was also processed by γ-secretase. We identified the BACE1 cleavage site of NCAM1 (at Glu 671) and NCAM2 (at Glu 663) using mass spectrometry and site-directed mutagenesis. Next, we assessed BACE1-mediated processing of NCAM1 and NCAM2 in the mouse brain during aging. NCAM1 and NCAM2 were cleaved in the olfactory bulb of BACE1+/+ but not BACE1−/− mice at postnatal day 10 (P10), 4 and 12 months of age. In the hippocampus, a BACE1-specific soluble fragment of NCAM1 (sNCAM1β) was only detected at P10. However, we observed an accumulation of full-length NCAM1 in hippocampal synaptosomes in 4-month-old BACE1−/− mice. We also found that polysialylated NCAM1 (PSA-NCAM1) levels were increased in BACE1−/− mice at P10 and demonstrated that BACE1 cleaves both NCAM1 and PSA-NCAM1 in vitro . In contrast, we did not find evidence for BACE1-dependent NCAM2 processing in the hippocampus at any age analyzed. In summary, our data demonstrate that BACE1 differentially processes NCAM1 and NCAM2 depending on the region of brain, subcellular localization, and age in vivo .

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Mouse brain proteomics establishes MDGA1 and CACHD1 as in vivo substrates of the Alzheimer protease BACE1

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 25 publications

References 92 publications

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

MDGA1 negatively regulates amyloid precursor protein–mediated synapse inhibition in the hippocampus

Distinct brain regional proteome changes in the rTg‐DI rat model of cerebral amyloid angiopathy

Spatiotemporal processing of neural cell adhesion molecules 1 and 2 by BACE1 in vivo

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