Amyloid precursor protein 𝛽CTF accumulates in synapses in sporadic and genetic forms of Alzheimer's disease.
APP 𝛽-C-terminal fragment
Down syndrome
amyloid precursor protein
amyloid-β
array tomography
autosomal-dominant Alzheimer's disease
sporadic Alzheimer's disease
synapsis
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
02 2023
02 2023
Historique:
revised:
21
12
2022
received:
11
05
2022
accepted:
21
01
2023
pubmed:
27
1
2023
medline:
3
3
2023
entrez:
26
1
2023
Statut:
ppublish
Résumé
Amyloid precursor protein (APP) 𝛽-C-terminal fragment (𝛽CTF) may have a neurotoxic role in Alzheimer's disease (AD). 𝛽CTF accumulates in the brains of patients with sporadic (SAD) and genetic forms of AD. Synapses degenerate early during the pathogenesis of AD. We studied whether the 𝛽CTF accumulates in synapses in SAD, autosomal dominant AD (ADAD) and Down syndrome (DS). We used array tomography to determine APP at synapses in human AD tissue. We measured 𝛽CTF, A𝛽40, A𝛽42 and phosphorylated tau181 (p-tau181) concentrations in brain homogenates and synaptosomes of frontal and temporal cortex of SAD, ADAD, DS and controls. APP colocalised with pre- and post-synaptic markers in human AD brains. APP 𝛽CTF was enriched in AD synaptosomes. We demonstrate that 𝛽CTF accumulates in synapses in SAD, ADAD and DS. This finding might suggest a role for 𝛽CTF in synapse degeneration. Therapies aimed at mitigating 𝛽CTF accumulation could be potentially beneficial in AD.
Substances chimiques
Amyloid beta-Protein Precursor
0
Amyloid beta-Peptides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e12879Informations de copyright
© 2023 British Neuropathological Society.
Références
Lleó A, Saura CA. γ-Secretase substrates and their implications for drug development in Alzheimer's disease. Curr Top Med Chem. 2011;11(12):1513-1527. doi:10.2174/156802611795861004
Dyrks T, Weidemann A, Multhaup G, et al. Identification, transmembrane orientation and biogenesis of the amyloid A4 precursor of Alzheimer's disease. EMBO J. 1988;7(4):949-957.
Lleó A, Cavedo E, Parnetti L, et al. Cerebrospinal fluid biomarkers in trials for Alzheimer and Parkinson diseases. Nat Rev Neurol. 2015;11(1):41-55. doi:10.1038/nrneurol.2014.232
Checler F, Afram E, Pardossi-Piquard R, Lauritzen I. Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99? J Biol Chem. 2021;296:100489. doi:10.1016/j.jbc.2021.100489
Pera M, Alcolea D, Sánchez-Valle R, et al. Distinct patterns of APP processing in the CNS in autosomal-dominant and sporadic Alzheimer disease. Acta Neuropathol. 2013;125(2):201-213. doi:10.1007/s00401-012-1062-9
Hébert SS, Horré K, Nicolaï L, et al. Loss of microRNA cluster miR-29a/b-1 in sporadic Alzheimer's disease correlates with increased BACE1/β-secretase expression. Proc Natl Acad Sci U S A. 2008;105(17):6415-6420. doi:10.1073/pnas.0710263105
Kim S, Sato Y, Mohan PS, et al. Evidence that the rab5 effector APPL1 mediates APP-βCTF-induced dysfunction of endosomes in down syndrome and Alzheimer's disease. Mol Psychiatry. 2016;21(5):707-716. doi:10.1038/mp.2015.97
Vaillant-Beuchot L, Mary A, Pardossi-Piquard R, et al. Accumulation of amyloid precursor protein C-terminal fragments triggers mitochondrial structure, function, and mitophagy defects in Alzheimer's disease models and human brains. Acta Neuropathol. 2021;141(1):39-65. doi:10.1007/s00401-020-02234-7
Pulina MV, Hopkins M, Haroutunian V, Greengard P, Bustos V. C99 selectively accumulates in vulnerable neurons in Alzheimer's disease. Alzheimer's and Dementia. 2019;16(2):1-11. doi:10.1016/j.jalz.2019.09.002
Gomez W, Morales R, Maracaja-Coutinho V, Parra V, Nassif M. Down syndrome and alzheimer's disease: common molecular traits beyond the amyloid precursor protein. Aging. 2020;12(1):1011-1033. doi:10.18632/aging.102677
Carmona-Iragui M, Alcolea D, Barroeta I, et al. Diagnostic and prognostic performance and longitudinal changes in plasma neurofilament light chain concentrations in adults with Down syndrome: a cohort study. Lancet Neurol. 2021;20(8):605-614. doi:10.1016/S1474-4422(21)00129-0
Fortea J, Vilaplana E, Carmona-Iragui M, et al. Clinical and biomarker changes of Alzheimer's disease in adults with Down syndrome: a cross-sectional study. Lancet. 2020;395(10242):1988-1997. doi:10.1016/S0140-6736(20)30689-9
Jiang Y, Mullaney KA, Peterhoff CM, et al. Alzheimer's-related endosome dysfunction in Down syndrome is Aβ-independent but requires APP and is reversed by BACE-1 inhibition. PNAS. 2009;107(4):1630-1635. doi:10.1073/pnas.0908953107
Lauritzen I, Pardossi-Piquard R, Bauer C, et al. The β-secretase-derived C-terminal fragment of βAPP, C99, but not Aβ, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus. J Neurosci. 2012;32(46):16243-16255. doi:10.1523/JNEUROSCI.2775-12.2012
Cavanagh C, Colby-Milley J, Bouvier D, et al. βCTF-correlated burst of hippocampal TNFα occurs at a very early, pre-plaque stage in the TgCRND8 mouse model of Alzheimer's disease. J Alzheimers Dis. 2013;36(2):233-238. doi:10.3233/JAD-122131
Mondragón-Rodríguez S, Gu N, Manseau F, Williams S. Alzheimer's transgenic model is characterized by very early brain network alterations and β-CTF fragment accumulation: reversal by β-secretase inhibition. Front Cell Neurosci. 2018;12:121. doi:10.3389/fncel.2018.00121
Kaur G, Pawlik M, Gandy SE, Ehrlich ME, Smiley JF, Levy E. Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein. Mol Psychiatry. 2017;22(7):981-989. doi:10.1038/mp.2016.189
Nalbantoglu J, Tirado-Santiago G, Lahsaïni A, et al. Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature. 1997;387(6632):500-505. doi:10.1038/387500a0
Lauritzen I, Pardossi-Piquard R, Bourgeois A, et al. Intraneuronal aggregation of the β-CTF fragment of APP (C99) induces Aβ-independent lysosomal-autophagic pathology. Acta Neuropathol. 2016;132(2):257-276. doi:10.1007/s00401-016-1577-6
Saura CA, Chen G, Malkani S, et al. Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice. J Neurosci. 2005;25(29):6755-6764. doi:10.1523/JNEUROSCI.1247-05.2005
Koffie RM, Hyman BT, Spires-Jones TL. Alzheimer's disease: synapses gone cold. Molecular Neurodegeneration. 2011;6(1):63. doi:10.1186/1750-1326-6-63
Neve RL, Robakis NK. Alzheimer's disease: a re-examination of the amyloid hypothesis. Trends Neurosci. 1998;21(1):15-19. doi:10.1016/S0166-2236(97)01168-5
Nelson PT, Alafuzoff I, Bigio EH, et al. Correlation of Alzheimer disease neuropathologic changes with cognitive status: a review of the literature NIH public access. J Neuropathol Exp Neurol. 2012;71(5):362-381. doi:10.1097/NEN.0b013e31825018f7
Tai HC, Serrano-Pozo A, Hashimoto T, Frosch MP, Spires-Jones TL, Hyman BT. The synaptic accumulation of hyperphosphorylated tau oligomers in alzheimer disease is associated with dysfunction of the ubiquitin-proteasome system. Am J Pathol. 2012;181(4):1426-1435. doi:10.1016/j.ajpath.2012.06.033
DeVos SL, Corjuc BT, Oakley DH, et al. Synaptic tau seeding precedes tau pathology in human Alzheimer's disease brain. Front Neurosci. 2018;12:267. doi:10.3389/fnins.2018.00267
Colom-Cadena M, Gelpi E, Charif S, et al. Confluence of -Synuclein, tau, and A-amyloid pathologies in dementia with Lewy bodies. J Neuropathol Exp Neurol. 2013;72(12):1203-1212. doi:10.1097/NEN.0000000000000018
Montine TJ, Phelps CH, Beach TG, et al. National Institute on Aging-Alzheimer's Association guidelines for the neuropathologic assessment of Alzheimer's disease: a practical approach NIH public access. Acta Neuropathol. 2012;123(1):1-11. doi:10.1007/s00401-011-0910-3
Kay KR, Smith C, Wright AK, et al. Studying synapses in human brain with array tomography and electron microscopy. Nat Protoc. 2013;8(7):1366-1380. doi:10.1038/nprot.2013.078.Studying
Colom-Cadena M, Pegueroles J, Herrmann AG, et al. Synaptic phosphorylated a-synuclein in dementia with Lewy bodies. Brain. 2017;1(140):3204-3214. doi:10.1093/brain/awx275
Querol-Vilaseca M, Colom-Cadena M, Pegueroles J, et al. Nanoscale structure of amyloid- β plaques in Alzheimer’ s disease. Sci Rep. 2019;9(1):5181. doi:10.1038/s41598-019-41443-3
Pickett EK, Henstridge CM, Allison E, et al. Spread of tau down neural circuits precedes synapse and neuronal loss in the rTgTauEC mouse model of early Alzheimer's disease. Synapse. 2017;71(6):e21965. doi:10.1002/syn.21965
Lleó A, Núñez-Llaves R, Alcolea D, et al. Changes in synaptic proteins precede neurodegeneration markers in preclinical Alzheimer's disease cerebrospinal fluid. Mol Cell Proteomics. 2019;18(3):546-560. doi:10.1074/mcp.RA118.001290
Müller UC, Deller T, Korte M. Not just amyloid: physiological functions of the amyloid precursor protein family. Nat Rev Neurosci. 2017;18(5):281-298. doi:10.1038/nrn.2017.29
Wilhelm BG, Mandad S, Truckenbrodt S, et al. Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science. 2014;344(6187):1023-1028. doi:10.1126/science.1252884
Groemer T, Thiel C, Holt M, et al. Amyloid precursor protein is trafficked and secreted via synaptic vesicles. PLoS Genet. 2011;6(4):e18754. doi:10.1371/journal.pone.0018754
Lundgren JL, Ahmed S, Schedin-Weiss S, et al. ADAM10 and BACE1 are localized to synaptic vesicles. J Neurochem. 2015;135(3):606-615. doi:10.1111/jnc.13287
Laßek M, Weingarten J, Einsfelder U, Brendel P, Müller U, Volknandt W. Amyloid precursor proteins are constituents of the presynaptic active zone. J Neurochem. 2013;127(1):48-56. doi:10.1111/jnc.12358
Sawa M, Overk C, Becker A, et al. Impact of increased APP gene dose in Down syndrome and the Dp16 mouse model. Alzheimers Dement. 2021;18(6):1-32. doi:10.1002/alz.12463
Mitani Y, Yarimizu J, Saita K, et al. Differential effects between γ-secretase inhibitors and modulators on cognitive function in amyloid precursor protein-transgenic and nontransgenic mice. J Neurosci. 2012;32(6):2037-2050. doi:10.1523/JNEUROSCI.4264-11.2012
Pera M, Larrea D, Guardia-Laguarta C, et al. Increased localization of APP -C99 in mitochondria-associated ER membranes causes mitochondrial dysfunction in Alzheimer disease. EMBO J. 2017;36(22):3356-3371. doi:10.15252/embj.201796797
Yankner BA, Dawes LR, Fischer S, Villa-Komaroff L, Oster-Grantie ML, Neve RL. Neurotoxicity of a fragment of APP associated with AD. Science. 1989;245(4916):417-420. doi:10.1126/science.2474201
Jinno S, Araki K, Matsumoto Y, Suh YH, Yamamoto T. Selective apoptosis induction in the hippocampal mossy fiber pathway by exposure to CT105, the C-terminal fragment of Alzheimer's amyloid precursor protein. Brain Res. 2009;1249:68-78. doi:10.1016/j.brainres.2008.10.052
Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer's disease. Neuron. 2014;82(4):756-771. doi:10.1016/j.neuron.2014.05.004
Wenk GL. Neuropathologic changes in Alzheimer's disease. J Clin Psychiatry. 2003;64:7-10.
Perez-Nievas BG, Stein TD, Tai HC, et al. Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology. Brain. 2013;136(8):2510-2526. doi:10.1093/brain/awt171
Dujardin S, Commins C, Lathuiliere A, et al. Tau molecular diversity contributes to clinical heterogeneity in Alzheimer's disease. Nat Med. 2020;26(8):1256-1263. doi:10.1038/s41591-020-0938-9.Tau