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Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Abstract

Alzheimer’s disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.

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References

  1. Abramov E, Dolev I, Fogel H, Ciccotosto GD, Ruff E, Slutsky I (2009) Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 12:1567–1576. doi:10.1038/nn.2433

    CAS  Article  PubMed  Google Scholar 

  2. Ahmed RR, Holler CJ, Webb RL, Li F, Beckett TL, Murphy MP (2010) BACE1 and BACE2 enzymatic activities in Alzheimer’s disease. J Neurochem 112:1045–1053. doi:10.1111/j.1471-4159.2009.06528.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. Almkvist O, Basun H, Wagner SL, Rowe BA, Wahlund LO, Lannfelt L (1997) Cerebrospinal fluid levels of alpha-secretase-cleaved soluble amyloid precursor protein mirror cognition in a Swedish family with Alzheimer disease and a gene mutation. Arch Neurol 54:641–644

    CAS  Article  PubMed  Google Scholar 

  4. Anderson JJ, Holtz G, Baskin PP et al (1999) Reduced cerebrospinal fluid levels of alpha-secretase-cleaved amyloid precursor protein in aged rats: correlation with spatial memory deficits. Neuroscience 93:1409–1420 (pii: S0306-4522(99)00244-4)

    CAS  Article  PubMed  Google Scholar 

  5. Aurnhammer C, Haase M, Muether N et al (2012) Universal real-time PCR for the detection and quantification of adeno-associated virus serotype 2-derived inverted terminal repeat sequences. Human Gene Therapy Methods 23:18–28. doi:10.1089/hgtb.2011.034

    CAS  Article  PubMed  Google Scholar 

  6. Austin SA, Combs CK (2008) Mechanisms of microglial activation by amyloid precursor protein and its proteolytic fragments. In: Lane TE, Carson M, Bergmann C, Wyss-Coray T (eds) Central nervous system diseases and inflammation. Springer US, New York, pp 13–32

    Chapter  Google Scholar 

  7. Aydin D, Weyer SW, Muller UC (2012) Functions of the APP gene family in the nervous system: insights from mouse models. Exp Brain Res 217:423–434. doi:10.1007/s00221-011-2861-2

    CAS  Article  PubMed  Google Scholar 

  8. Barger SW, Harmon AD (1997) Microglial activation by Alzheimer amyloid precursor protein and modulation by apolipoprotein E. Nature 388:878–881. doi:10.1038/42257

    CAS  Article  PubMed  Google Scholar 

  9. Bell KF, Zheng L, Fahrenholz F, Cuello AC (2008) ADAM-10 over-expression increases cortical synaptogenesis. Neurobiol Aging 29:554–565. doi:10.1016/j.neurobiolaging.2006.11.004

    CAS  Article  PubMed  Google Scholar 

  10. Berger A, Lorain S, Josephine C et al (2015) Repair of rhodopsin mRNA by spliceosome-mediated RNA trans-splicing: a new approach for autosomal dominant retinitis pigmentosa. Mol Ther. doi:10.1038/mt.2015.11

    PubMed  PubMed Central  Google Scholar 

  11. Billings LM, Oddo S, Green KN, McGaugh JL, LaFerla FM (2005) Intraneuronal Abeta causes the onset of early Alzheimer’s disease-related cognitive deficits in transgenic mice. Neuron 45:675–688. doi:10.1016/j.neuron.2005.01.040

    CAS  Article  PubMed  Google Scholar 

  12. Bodles AM, Barger SW (2005) Secreted beta-amyloid precursor protein activates microglia via JNK and p38-MAPK. Neurobiol Aging 26:9–16. doi:10.1016/j.neurobiolaging.2004.02.022

    CAS  Article  PubMed  Google Scholar 

  13. Borchelt DR, Ratovitski T, van Lare J et al (1997) Accelerated amyloid deposition in the brains of transgenic mice coexpressing mutant presenilin 1 and amyloid precursor proteins. Neuron 19:939–945

    CAS  Article  PubMed  Google Scholar 

  14. Bour A, Little S, Dodart JC, Kelche C, Mathis C (2004) A secreted form of the beta-amyloid precursor protein (sAPP695) improves spatial recognition memory in OF1 mice. Neurobiol Learn Mem 81:27–38 (pii: S1074742703000716)

    CAS  Article  PubMed  Google Scholar 

  15. Caille I, Allinquant B, Dupont E et al (2004) Soluble form of amyloid precursor protein regulates proliferation of progenitors in the adult subventricular zone. Development 131:2173–2181

    CAS  Article  PubMed  Google Scholar 

  16. Casanova F, Carney PR, Sarntinoranont M (2014) Effect of needle insertion speed on tissue injury, stress, and backflow distribution for convection-enhanced delivery in the rat brain. PLoS One 9:e94919. doi:10.1371/journal.pone.0094919

    Article  PubMed  PubMed Central  Google Scholar 

  17. Claasen AM, Guevremont D, Mason-Parker SE et al (2009) Secreted amyloid precursor protein-alpha upregulates synaptic protein synthesis by a protein kinase G-dependent mechanism. Neurosci Lett 460:92–96. doi:10.1016/j.neulet.2009.05.040

    CAS  Article  PubMed  Google Scholar 

  18. Copanaki E, Chang S, Vlachos A et al (2010) sAPPalpha antagonizes dendritic degeneration and neuron death triggered by proteasomal stress. Mol Cell Neurosci 44:386–393. doi:10.1016/j.mcn.2010.04.007

    CAS  Article  PubMed  Google Scholar 

  19. Corrigan F, Vink R, Blumbergs PC, Masters CL, Cappai R, van den Heuvel C (2012) sAPPalpha rescues deficits in amyloid precursor protein knockout mice following focal traumatic brain injury. J Neurochem 122:208–220. doi:10.1111/j.1471-4159.2012.07761.x

    CAS  Article  PubMed  Google Scholar 

  20. Cousins SL, Hoey SE, Anne Stephenson F, Perkinton MS (2009) Amyloid precursor protein 695 associates with assembled NR2A- and NR2B-containing NMDA receptors to result in the enhancement of their cell surface delivery. J Neurochem 111:1501–1513. doi:10.1111/j.1471-4159.2009.06424.x

    CAS  Article  PubMed  Google Scholar 

  21. Cousins SL, Innocent N, Stephenson FA (2013) Neto1 associates with the NMDA receptor/amyloid precursor protein complex. J Neurochem 126:554–564. doi:10.1111/jnc.12280

    CAS  Article  PubMed  Google Scholar 

  22. Dobrowolska JA, Kasten T, Huang Y et al (2014) Diurnal patterns of soluble amyloid precursor protein metabolites in the human central nervous system. PLoS One 9:e89998. doi:10.1371/journal.pone.0089998

    Article  PubMed  PubMed Central  Google Scholar 

  23. Doody RS, Raman R, Farlow M et al (2013) A phase 3 trial of semagacestat for treatment of Alzheimer’s disease. N Engl J Med 369:341–350. doi:10.1056/NEJMoa1210951

    CAS  Article  PubMed  Google Scholar 

  24. Drummond ES, Muhling J, Martins RN, Wijaya LK, Ehlert EM, Harvey AR (2013) Pathology associated with AAV mediated expression of beta amyloid or C100 in adult mouse hippocampus and cerebellum. PLoS One 8:e59166. doi:10.1371/journal.pone.0059166

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. Endres K, Fahrenholz F (2012) Regulation of alpha-secretase ADAM10 expression and activity. Exp Brain Res 217:343–352. doi:10.1007/s00221-011-2885-7

    CAS  Article  PubMed  Google Scholar 

  26. Frank S, Burbach GJ, Bonin M et al (2008) TREM2 is upregulated in amyloid plaque-associated microglia in aged APP23 transgenic mice. Glia 56:1438–1447. doi:10.1002/glia.20710

    Article  PubMed  Google Scholar 

  27. Furukawa K, Barger SW, Blalock EM, Mattson MP (1996) Activation of K + channels and suppression of neuronal activity by secreted beta-amyloid-precursor protein. Nature 379:74–78. doi:10.1038/379074a0

    CAS  Article  PubMed  Google Scholar 

  28. Furukawa K, Mattson MP (1998) Secreted amyloid precursor protein alpha selectively suppresses N-methyl-d-aspartate currents in hippocampal neurons: involvement of cyclic GMP. Neuroscience 83:429–438 (pii: S0306452297003989)

    CAS  Article  PubMed  Google Scholar 

  29. Furukawa K, Sopher BL, Rydel RE et al (1996) Increased activity-regulating and neuroprotective efficacy of alpha-secretase-derived secreted amyloid precursor protein conferred by a C-terminal heparin-binding domain. J Neurochem 67:1882–1896

    CAS  Article  PubMed  Google Scholar 

  30. Goodman Y, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect hippocampal neurons against amyloid beta-peptide-induced oxidative injury. Exp Neurol 128:1–12. doi:10.1006/exnr.1994.1107

    CAS  Article  PubMed  Google Scholar 

  31. Guerreiro R, Wojtas A, Bras J et al (2013) TREM2 variants in Alzheimer’s disease. N Engl J Med 368:117–127. doi:10.1056/NEJMoa1211851

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. Heneka MT, Kummer MP, Stutz A et al (2013) NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature 493:674–678. doi:10.1038/nature11729

    CAS  Article  PubMed  Google Scholar 

  33. Hick M, Herrmann U, Weyer SW et al (2015) Acute function of secreted amyloid precursor protein fragment APPsalpha in synaptic plasticity. Acta Neuropathol 129:21–37. doi:10.1007/s00401-014-1368-x

    CAS  Article  PubMed  Google Scholar 

  34. Hoe HS, Lee HK, Pak DT (2012) The upside of APP at synapses. CNS Neurosci Ther 18:47–56. doi:10.1111/j.1755-5949.2010.00221.x

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  35. Hoey SE, Williams RJ, Perkinton MS (2009) Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci 29:4442–4460. doi:10.1523/JNEUROSCI.6017-08.2009

    CAS  Article  PubMed  Google Scholar 

  36. Holsinger RM, McLean CA, Beyreuther K, Masters CL, Evin G (2002) Increased expression of the amyloid precursor beta-secretase in Alzheimer’s disease. Ann Neurol 51:783–786. doi:10.1002/ana.10208

    CAS  Article  PubMed  Google Scholar 

  37. Ishida A, Furukawa K, Keller JN, Mattson MP (1997) Secreted form of beta-amyloid precursor protein shifts the frequency dependency for induction of LTD, and enhances LTP in hippocampal slices. NeuroReport 8:2133–2137

    CAS  Article  PubMed  Google Scholar 

  38. Jankowsky JL, Fadale DJ, Anderson J et al (2004) Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet 13:159–170. doi:10.1093/hmg/ddh019

    CAS  Article  PubMed  Google Scholar 

  39. Jay TR, Miller CM, Cheng PJ et al (2015) TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J Exp Med 212:287–295. doi:10.1084/jem.20142322

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  40. Jonsson T, Stefansson H, Steinberg S et al (2013) Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med 368:107–116. doi:10.1056/NEJMoa1211103

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. Kamphuis W, Mamber C, Moeton M et al (2012) GFAP isoforms in adult mouse brain with a focus on neurogenic astrocytes and reactive astrogliosis in mouse models of Alzheimer disease. PLoS One 7:e42823. doi:10.1371/journal.pone.0042823

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. Klevanski M, Saar M, Baumkotter F, Weyer SW, Kins S, Muller UC (2014) Differential role of APP and APLPs for neuromuscular synaptic morphology and function. Mol Cell Neurosci 61C:201–210. doi:10.1016/j.mcn.2014.06.004

    Article  Google Scholar 

  43. Kogel D, Deller T, Behl C (2012) Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging. Exp Brain Res 217:471–479. doi:10.1007/s00221-011-2932-4

    Article  PubMed  Google Scholar 

  44. Lannfelt L, Basun H, Wahlund LO, Rowe BA, Wagner SL (1995) Decreased alpha-secretase-cleaved amyloid precursor protein as a diagnostic marker for Alzheimer’s disease. Nat Med 1:829–832

    CAS  Article  PubMed  Google Scholar 

  45. Lassek M, Weingarten J, Einsfelder U, Brendel P, Muller U, Volknandt W (2013) Amyloid precursor proteins are constituents of the presynaptic active zone. J Neurochem 127:48–56. doi:10.1111/jnc.12358

    CAS  PubMed  Google Scholar 

  46. Lee KJ, Moussa CE, Lee Y et al (2010) Beta amyloid-independent role of amyloid precursor protein in generation and maintenance of dendritic spines. Neuroscience 169:344–356. doi:10.1016/j.neuroscience.2010.04.078

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. Leissring MA, Farris W, Chang AY et al (2003) Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 40:1087–1093

    CAS  Article  PubMed  Google Scholar 

  48. Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA (2005) Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J 24:2944–2955. doi:10.1038/sj.emboj.7600757

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. Li ZW, Stark G, Gotz J et al (1996) Generation of mice with a 200-kb amyloid precursor protein gene deletion by Cre recombinase-mediated site-specific recombination in embryonic stem cells. Proc Natl Acad Sci USA 93:6158–6162

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. Lichtenthaler SF, Haass C, Steiner H (2011) Regulated intramembrane proteolysis–lessons from amyloid precursor protein processing. J Neurochem 117:779–796. doi:10.1111/j.1471-4159.2011.07248.x

    CAS  Article  PubMed  Google Scholar 

  51. Lu B, Nagappan G, Guan X, Nathan PJ, Wren P (2013) BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases. Nat Rev Neurosci 14:401–416. doi:10.1038/nrn3505

    CAS  Article  PubMed  Google Scholar 

  52. Marcello E, Gardoni F, Mauceri D et al (2007) Synapse-associated protein-97 mediates alpha-secretase ADAM10 trafficking and promotes its activity. J Neurosci 27:1682–1691. doi:10.1523/JNEUROSCI.3439-06.2007

    CAS  Article  PubMed  Google Scholar 

  53. Meziane H, Dodart JC, Mathis C et al (1998) Memory-enhancing effects of secreted forms of the beta-amyloid precursor protein in normal and amnestic mice. Proc Natl Acad Sci USA 95:12683–12688

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  54. Mileusnic R, Lancashire CL, Rose SP (2004) The peptide sequence Arg-Glu-Arg, present in the amyloid precursor protein, protects against memory loss caused by A beta and acts as a cognitive enhancer. Eur J Neurosci 19:1933–1938. doi:10.1111/j.1460-9568.2004.03276.x

    CAS  Article  PubMed  Google Scholar 

  55. Milosch N, Tanriover G, Kundu A et al (2014) Holo-APP and G-protein-mediated signaling are required for sAPPalpha-induced activation of the Akt survival pathway. Cell Death Dis 5:e1391. doi:10.1038/cddis.2014.352

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. Miners JS, Barua N, Kehoe PG, Gill S, Love S (2011) Abeta-degrading enzymes: potential for treatment of Alzheimer disease. J Neuropathol Exp Neurol 70:944–959. doi:10.1097/NEN.0b013e3182345e46

    CAS  Article  PubMed  Google Scholar 

  57. Mucke L, Abraham CR, Masliah E (1996) Neurotrophic and neuroprotective effects of hAPP in transgenic mice. Ann N Y Acad Sci 777:82–88

    CAS  Article  PubMed  Google Scholar 

  58. Murakami N, Yamaki T, Iwamoto Y et al (1998) Experimental brain injury induces expression of amyloid precursor protein, which may be related to neuronal loss in the hippocampus. J Neurotrauma 15:993–1003

    CAS  Article  PubMed  Google Scholar 

  59. Nhan HS, Chiang K, Koo EH (2015) The multifaceted nature of amyloid precursor protein and its proteolytic fragments: friends and foes. Acta Neuropathol 129:1–19. doi:10.1007/s00401-014-1347-2

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  60. Obregon D, Hou H, Deng J et al (2012) Soluble amyloid precursor protein-alpha modulates beta-secretase activity and amyloid-beta generation. Nat Commun 3:777. doi:10.1038/ncomms1781ncomms1781

    Article  PubMed  PubMed Central  Google Scholar 

  61. Pennanen L, Wolfer DP, Nitsch RM, Gotz J (2006) Impaired spatial reference memory and increased exploratory behavior in P301L tau transgenic mice. Genes Brain Behav 5:369–379. doi:10.1111/j.1601-183X.2005.00165.x

    CAS  Article  PubMed  Google Scholar 

  62. Prokop S, Miller KR, Heppner FL (2013) Microglia actions in Alzheimer’s disease. Acta Neuropathol 126:461–477

    CAS  Article  PubMed  Google Scholar 

  63. Prox J, Rittger A, Saftig P (2012) Physiological functions of the amyloid precursor protein secretases ADAM10, BACE1, and Presenilin. Exp Brain Res 217:331–341. doi:10.1007/s00221-011-2952-0

    CAS  Article  PubMed  Google Scholar 

  64. Ramirez MJ, Heslop KE, Francis PT, Rattray M (2001) Expression of amyloid precursor protein, tau and presenilin RNAs in rat hippocampus following deafferentation lesions. Brain Res 907:222–232

    CAS  Article  PubMed  Google Scholar 

  65. Ring S, Weyer SW, Kilian SB et al (2007) The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice. J Neurosci 27:7817–7826. doi:10.1523/JNEUROSCI.1026-07.2007

    CAS  Article  PubMed  Google Scholar 

  66. Roch JM, Masliah E, Roch-Levecq AC et al (1994) Increase of synaptic density and memory retention by a peptide representing the trophic domain of the amyloid beta/A4 protein precursor. Proc Natl Acad Sci USA 91:7450–7454

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  67. Roozendaal B, Phillips RG, Power AE, Brooke SM, Sapolsky RM, McGaugh JL (2001) Memory retrieval impairment induced by hippocampal CA3 lesions is blocked by adrenocortical suppression. Nat Neurosci 4:1169–1171. doi:10.1038/nn766

    CAS  Article  PubMed  Google Scholar 

  68. Savonenko A, Xu GM, Melnikova T et al (2005) Episodic-like memory deficits in the APPswe/PS1dE9 mouse model of Alzheimer’s disease: relationships to beta-amyloid deposition and neurotransmitter abnormalities. Neurobiol Dis 18:602–617. doi:10.1016/j.nbd.2004.10.022

    CAS  Article  PubMed  Google Scholar 

  69. Selkoe DJ (2002) Alzheimer’s disease is a synaptic failure. Science 298:789–791. doi:10.1126/science.1074069

    CAS  Article  PubMed  Google Scholar 

  70. Shankar GM, Bloodgood BL, Townsend M, Walsh DM, Selkoe DJ, Sabatini BL (2007) Natural oligomers of the Alzheimer amyloid-beta protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway. J Neurosci 27:2866–2875. doi:10.1523/JNEUROSCI.4970-06.2007

    CAS  Article  PubMed  Google Scholar 

  71. Shankar GM, Li S, Mehta TH et al (2008) Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14:837–842. doi:10.1038/nm1782

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  72. Smith-Swintosky VL, Pettigrew LC, Craddock SD, Culwell AR, Rydel RE, Mattson MP (1994) Secreted forms of beta-amyloid precursor protein protect against ischemic brain injury. J Neurochem 63:781–784

    CAS  Article  PubMed  Google Scholar 

  73. Spires-Jones T, Knafo S (2012) Spines, plasticity, and cognition in Alzheimer’s model mice. Neural Plast 2012:319836. doi:10.1155/2012/319836

    PubMed  PubMed Central  Google Scholar 

  74. Suh J, Choi SH, Romano DM et al (2013) ADAM10 missense mutations potentiate beta-amyloid accumulation by impairing prodomain chaperone function. Neuron 80:385–401. doi:10.1016/j.neuron.2013.08.035

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  75. Tang W, Ehrlich I, Wolff SB et al (2009) Faithful expression of multiple proteins via 2A-peptide self-processing: a versatile and reliable method for manipulating brain circuits. J Neurosci 29:8621–8629. doi:10.1523/JNEUROSCI.0359-09.2009

    CAS  Article  PubMed  Google Scholar 

  76. Taylor CJ, Ireland DR, Ballagh I et al (2008) Endogenous secreted amyloid precursor protein-alpha regulates hippocampal NMDA receptor function, long-term potentiation and spatial memory. Neurobiol Dis 31:250–260. doi:10.1016/j.nbd.2008.04.011

    CAS  Article  PubMed  Google Scholar 

  77. Terry RD, Masliah E, Salmon DP et al (1991) Physical basis of cognitive alterations in Alzheimer’s disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol 30:572–580. doi:10.1002/ana.410300410

    CAS  Article  PubMed  Google Scholar 

  78. Thornton E, Vink R, Blumbergs PC, Van Den Heuvel C (2006) Soluble amyloid precursor protein alpha reduces neuronal injury and improves functional outcome following diffuse traumatic brain injury in rats. Brain Res 1094:38–46. doi:10.1016/j.brainres.2006.03.107

    CAS  Article  PubMed  Google Scholar 

  79. Van den Heuvel C, Blumbergs PC, Finnie JW et al (1999) Upregulation of amyloid precursor protein messenger RNA in response to traumatic brain injury: an ovine head impact model. Exp Neurol 159:441–450. doi:10.1006/exnr.1999.7150

    Article  PubMed  Google Scholar 

  80. Vassar R, Kuhn PH, Haass C et al (2014) Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem 130:4–28. doi:10.1111/jnc.12715

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. Villemagne VL, Burnham S, Bourgeat P et al (2013) Amyloid beta deposition, neurodegeneration, and cognitive decline in sporadic Alzheimer’s disease: a prospective cohort study. Lancet Neurol 12:357–367. doi:10.1016/S1474-4422(13)70044-9

    CAS  Article  PubMed  Google Scholar 

  82. Wang Y, Cella M, Mallinson K et al (2015) TREM2 lipid sensing sustains the microglial response in an Alzheimer’s disease model. Cell 160:1061–1071. doi:10.1016/j.cell.2015.01.049

    CAS  Article  PubMed  Google Scholar 

  83. Wang Z, Wang B, Yang L et al (2009) Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. J Neurosci 29:10788–10801. doi:10.1523/JNEUROSCI.2132-09.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. Weyer SW, Klevanski M, Delekate A et al (2011) APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP. EMBO J 30:2266–2280. doi:10.1038/emboj.2011.119

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  85. Weyer SW, Zagrebelsky M, Herrmann U et al (2014) Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsalpha expression. Acta Neuropathol Commun 2:36. doi:10.1186/2051-5960-2-36

    Article  PubMed  PubMed Central  Google Scholar 

  86. Wilhelm BG, Mandad S, Truckenbrodt S et al (2014) Composition of isolated synaptic boutons reveals the amounts of vesicle trafficking proteins. Science 344:1023–1028. doi:10.1126/science.1252884

    CAS  Article  PubMed  Google Scholar 

  87. Xiong H, Callaghan D, Wodzinska J et al (2011) Biochemical and behavioral characterization of the double transgenic mouse model (APPswe/PS1dE9) of Alzheimer’s disease. Neurosci Bull 27:221–232. doi:10.1007/s12264-011-1015-7

    CAS  Article  PubMed  Google Scholar 

  88. Yang L, Wang Z, Wang B, Justice NJ, Zheng H (2009) Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity. J Neurosci 29:15660–15668. doi:10.1523/JNEUROSCI.4104-09.2009

    CAS  Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This work was supported by the Deutsche Forschungsgemeinschaft Grants (MU 1457/9-1, 9-2 to UCM; KO 1674/3-1, 3-2 to MK), the ERA-Net Neuron (01EW1305A to CJB, NC and UCM), and the LOEWE Center for Cell and Gene Therapy Frankfurt funded by Hessisches Ministerium für Wissenschaft und Kunst (III L 4- 518/17.004 (2010)) to CJB.

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Correspondence to Nathalie Cartier or Ulrike C. Müller.

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R. Fol and J. Braudeau are joint first authors.

N. Cartier and U. C. Müller are joint senior authors.

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Fol, R., Braudeau, J., Ludewig, S. et al. Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model. Acta Neuropathol 131, 247–266 (2016). https://doi.org/10.1007/s00401-015-1498-9

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Keywords

  • Alzheimer
  • Gene therapy
  • Amyloid precursor protein
  • APPsα
  • Synaptic plasticity
  • Spines
  • Behavior
  • Microglia
  • AAV