Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by extracellular accumulation of amyloid deposits. Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor whose levels have been shown to be decreased in AD brains. BDNF supplementation can offer improvement in the course of AD. However, the means of assessment are still relatively limited. In the present study, 1H-MRS was used to evaluate the therapeutic effects of bilateral intraventricular BDNF infusion into Alzheimer’s disease APP/PS1 double transgenic mice. For comparison to the 1H-MRS observations, Fluoro-Jade B staining and immunofluorescence for beta amyloid peptides (Aβ), glial fibrillary acidic protein, and tropomyosin-related kinase B (TrkB) were also performed. Our results showed that N-acetylaspartate (NAA) levels increased and myoinositol levels decreased in the BDNF group compared with the PBS group. However, the BDNF group NAA level was still lower than the control group at 6 weeks after infusion. These changes correlated with increased immunoreactivity for TrkB, decreased compact Aβ peptide containing plaques, and decreased Fluoro-Jade B-positive cells in the BDNF-infused mice compared to vehicle controls. These findings demonstrate that 1H-MRS may be a promising means of evaluating the therapeutic effects of BDNF on AD.
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References
Abraham CR (2001) Reactive astrocytes and alpha1-antiehymotrypsin in Alzheimer’s disease. Neurobiol Aging 22(6):931–936
Behar KL, den Hollander JA, Stromski ME, Ogino T, Shulman RG, Petroff OA, Prichard JW (1983) High resolution 1H-MRS study of cerebral hypoxia in vivo. Proc Natl Acad Sci USA 80(16):4945–4948
Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, Yamasaki TR, Poon WW, Green KN, LaFerla FM (2009) Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A 106(32):13594–13599
Chen SQ, Wang PJ, Ten GJ, Zhan W, Li MH, Zang FC (2009) Role of myo-inositol by magnetic resonance spectroscopy in early diagnosis of Alzheimer’s disease in APP/PS1 transgenic mice. Dement Geriatr Cogn Disord 28(6):558–566
Choi JK, Carreras I, Dedeoglu A, Jenkins BG (2010) Detection of increased scyllo-inositol in brain with magnetic resonance spectroscopy after dietary supplementation in Alzheimer’s disease mouse models. Neuropharmacology 59(4–5):353–357
Cummings JL (2003) Alzheimer’s disease: from molecular biology to neuropsychiatry. Semin Clin Neuropsychiatry 8(1):31–36
den Heijer T, Sijens PE, Prins ND, Hofman A, Koudstaal PJ, Oudkerk M, Breteler MM (2006) MR spectroscopy of brain white matter in the prediction of dementia. Neurology 66(4):540–544
Elliott RC, Black IB, Dreyfus CF (2001) Dregfus, Differential regulation of p75 and trkB mRNA expression after depolarizing stimuli or BDNF treatment in basal forebrain neuron cultures. J Neurosci Res 66(1):83–88
Falini A, Bozzali M, Magnani G, Pero G, Gambini A, Benedetti B, Mossini R, Franceschi M, Comi G, Scotti G, Filippi M (2005) A whole brain MR spectroscopy study from patients with Alzheimer’s disease and mild cognitive impairment. NeuroImage 26(4):1159–1163
Garzon D, Yu G, Fahnestock M (2002) Fahnestock M. A new brain-derived neurotrophic factor transcript and decrease in brain-derived neurotrophie factor transcripts 1, 2 and 3 in Alzheimer's disease parietal cortex. J Neurochemistry 82(5):1058–1064
Jankowsky JL, Slunt HH, Gonzales V, Jenkins NA, Copeland NG, Borchelt DR (2004) APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1. Neurobiol Aging 25(77):885–892
Jellinger KA (2006) Alzheimer 100-highlights in the history of Alzheimer research. J Neural Transm 113(11):1603–1623
Jessen F, Traeber F, Freymann K, Maier W, Schild HH, Block W (2006) Treatment monitoring and response prediction with proton MR spectroscopy in AD. Neurology 67(3):528–530
Jones RS, Waldman AD (2004) 1H-MRS evaluation of metabolism in Alzheimer’s disease and vascular dementia. Neurol Res 26(5):488–495
Kantarci K, Petersen RC, Boeve BF, Knopman DS, Tang-Wai DF, O'Brien PC, Weigand SD, Edland SD, Smith GE, Ivnik RJ, Ferman TJ, Tangalos EG, Jack CR Jr (2004) 1H MR spectroscopy in common dementias. Neurology 63(8):1393–1398
Karlawish JH, Casarett DJ, James BD, Xie SX, Kim SY (2005) The ability of persons with Alzheimer disease (AD) to make a decision about taking an AD treatment. Neurology 64(9):1514–1519
Klein RL, Muir D, King MA, Peel AL, Zolotukhin S, Möller JC, Krüttgen A, Heymach JV Jr, Muzyczka N, Meyer EM (1999) Long-term actions of vector-derived nerve growth factor or brain-derived neurotrophic factor on choline acetyltransferase and TrK receptor levels in the adult rat basal forebrain. Neuroscience 90(3):815–821
Kiyota T, Ingraham KL, Jacobsen MT, Xiong H, Ikezu T (2011) FGF2 gene transfer restores hippocampal functions in mouse models of Alzheimer’s disease and has therapeutic implications for neurocognitive disorders. Proc Natl Acad Sci U S A 108(49):E1339–1348
Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, Bartels M, Buchkremer G, Schott K (2006) Stage-dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm 113(9):1217–1224
Marjanska M, Curran GL, Wengenack TM, Henry PG, Bliss RL, Poduslo JF, Jack CR Jr, Ugurbil K, Garwood M (2005) Monitoring disease progression in transgenic mouse models of Alzheimer’s disease with proton magnetic resonance spectroscopy. Proc Natl Acad Sci U S A 102(33):11906–11910
Mrak RE, Sheng JG, Griffin WS (1996) Correlation of astrocytic S100 beta expression with dystrophic neurites in amyloid plaques of Alzheimer’ disease. J Neuropathol Exp Neurol 55(33):273–279
Modrego PJ, Fayed N, Errea JM, Rios C, Pina MA, Sarasa M (2010) Memantine versus donepezil in mild to moderate Alzheimer’s disease: a randomized trial with magnetic resonance spectroscopy. Eur J Neurol 17(3):405–412
Murer MG, Yan Q, Raisman-Vozari R (2001) Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol 63(1):71–124
Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH (2009) Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med 15(3):331–337
Parihar MS, Hemnani T (2004) Alzheimer’s disease pathogenesis and therapeutic interventions. J Clin Neurosci 11(5):456–467
Peng S, Wuu J, Mufson EJ, Fahnestock M (2005) Precursor form of brain-derived neurotrophic factor and mature brain-derived neurotrophic factor are decreased in the pre-clinical stages of Alzheimer’s disease. J Neurochem 93(6):1412–1421
Selkoe DJ (2001) Alzheimer’s disease: genes, proteins, and therapy. Physiol Rev 81(2):741–766
Soares DP, Law M (2009) Magnetic resonance spectroscopy of the brain: review of metabolites and clinical applications. Clin Radiol 64(1):12–21
Schmued LC, Albertson C, Slikker W Jr (1997) Fluoro-Jade: a novel fluorochrome for the sensitive and reliable histochemical localization of neuronal degeneration. Brain Res 751(1):37–46
Schmued LC, Hopkins KJ (2000) Fluoro-Jade B: a high affinity fluorescent marker for the localization of neuronal degeneration. Brain Res 874(2):123–130
Schaeffer EL, Novaes BA, da Silva ER, Skaf HD, Mendes-Neto AG (2009) Strategies to promote differentiation of newborn neurons into mature functional cells in Alzheimer brain. Prog Neuro-Psychopharmacol Biol Psychiatry 33(7):1087–1102
Tuszynski MH, Thal L, Pay M, Salmon DP, Hoi Sang U, Bakay R, Patel P, Blesch A, Vahlsing HL, Ho G, Tong G, Potkin SG, Fallon J, Hansen L, Mufson EJ, Kordower JH, Gall C, Conner J (2005) A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nat Med 11(5):551–555
Valenzuela MJ, Sachdev P (2001) Magnetic resonance spectroscopy in AD. Neurology 56(5):592–598
Woo DC, Lee SH, Lee DW, Kim SY, Kim GY, Rhim HS, Choi CB, Kim HY, Lee CU, Choe BY (2010) Regional metabolic alteration of Alzheimer’s disease in mouse brain expressing mutant human APP-PS1 by 1H HR-MAS. Behav Brain Res 211(1):125–131
Youdim MB, Buccafusco JJ (2005) Multi-functional drugs for various CNS targets in the treatment of neurodegenerative disorders. Trends Pharmacol Sci 26(1):27–35
Yamamoto M, Horiba M, Buescher JL, Huang D, Gendelman HE, Ransohoff RM, Ikezu T (2005) Overexpression of monocyte chemotactic protein-1/CCL2 in beta-amyloid precursor protein transgenic mice show accelerated diffuse beta amyloid deposition. Am J Pathol 166(5):1475–1485
Xuan AG, Long DH, Gu HG, Yang DD, Hong LP, Leng SL (2008) Protective effects of transplanted neural stem cells on the brain of Alzheimer’s disease rats. Neurosci Lett 440(3):331–335
Zarranz J (2004) From empiricism to neuroscience in Alzheimer’s disease. Rev Neurol 39(6):576–582
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This research was supported by grants from National Natural Science Foundation of China (81171297; 81200934).
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Zhang, W., Wang, Pj., Li, Mh. et al. 1H-MRS Assessment of the Therapeutic Effect of Bilateral Intraventricular BDNF Infusion into APP/PS1 Double Transgenic Mice. J Mol Neurosci 50, 434–442 (2013). https://doi.org/10.1007/s12031-013-9951-5
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DOI: https://doi.org/10.1007/s12031-013-9951-5