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Yoshiyama Y, Higuchi M, Zhang B, Huang SM, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM. Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.
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Anti-inflammatories for AD—Time for Consideration of the Next Generation?
This news article, discussing the impressive results reported by Yasumasa Yoshiyama, Virginia Lee, John Trojanowski, and their colleagues from the University of Pennsylvania, is most timely, and its importance should not be underestimated by the Alzheimer research community. For it represents now yet another new approach to AD that utilizes a potent and novel anti-inflammatory and reports rather startlingly positive, if preliminary, data.
This approach, using the macrolactam immunosuppressive FK506, joins the promising preliminary results reported by Dodel and his colleagues in Bonn [1], by Norman Relkin and his colleagues from Weill-Cornell using IVIG [2], and our pilot results using perispinal etanercept [3] in suggesting that the use of novel and biologic anti-inflammatories may merit serious consideration for further investigation as primary AD therapeutics.
The Penn group’s findings of early synaptic dysfunction are congruous with increasing evidence linking TNFα and other inflammatory mechanisms with synaptic dysfunction in AD [4-12]. My own findings of rapid improvement, within minutes, in verbal fluency, affect, and attention following perispinal etanercept [3,13] (some results as yet unpublished) are perhaps best explained by the known effects of TNFα on synaptic transmission and synaptic scaling [14-18].
Taken together, all of the above constitute support for the Penn group’s conclusion in their new article that “it is plausible that neurodegenerative tauopathies could be ameliorated by pharmacologic modulation of neuroinflammation.”
It is most unfortunate that publication of this important new paper by the group at Penn should coincide with the untimely passing of Leon Thal, one of the legendary figures in Alzheimer research. Perhaps it may be of some comfort that Dr. Thal performed some of the seminal early research investigating pharmacologic anti-inflammatory approaches to AD [19-21]. If Lee and colleagues’ new clues to the potential efficacy of these next-generation anti-inflammatories survive the rigors of testing in randomized, controlled trials, then we will all owe an additional debt of gratitude to the efforts of those who started the AD research community looking in this direction.
See also:
McCaffrey P. Pilot Study Shows Promise of Passive Immunotherapy. Alzheimer Research Forum, April 14, 2005. See ARF related news story
Tobinick E, Shirinyan D, Gross H. TNF Modulation for Treatment of Alzheimer's Disease: Effects on Verbal Function. Abstract presented at the Days of Molecular Medicine Conference, Karolinska Institutet, Stockholm, Sweden, May 27, 2006.
References:
Dodel RC, Du Y, Depboylu C, Hampel H, Frölich L, Haag A, Hemmeter U, Paulsen S, Teipel SJ, Brettschneider S, Spottke A, Nölker C, Möller HJ, Wei X, Farlow M, Sommer N, Oertel WH. Intravenous immunoglobulins containing antibodies against beta-amyloid for the treatment of Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2004 Oct;75(10):1472-4. PubMed.
Tobinick E, Gross H, Weinberger A, Cohen H. TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006;8(2):25. PubMed.
Albensi BC, Mattson MP. Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000 Feb;35(2):151-9. PubMed.
Small DH, Mok SS, Bornstein JC. Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci. 2001 Aug;2(8):595-8. PubMed.
Beattie EC, Stellwagen D, Morishita W, Bresnahan JC, Ha BK, Von Zastrow M, Beattie MS, Malenka RC. Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. PubMed.
Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM. Triple-transgenic model of Alzheimer's disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron. 2003 Jul 31;39(3):409-21. PubMed.
Laferla FM, Oddo S. Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PubMed.
Stellwagen D, Beattie EC, Seo JY, Malenka RC. Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23;25(12):3219-28. PubMed.
Bell KF, Claudio Cuello A. Altered synaptic function in Alzheimer's disease. Eur J Pharmacol. 2006 Sep 1;545(1):11-21. PubMed.
Puzzo D, Palmeri A, Arancio O. Involvement of the nitric oxide pathway in synaptic dysfunction following amyloid elevation in Alzheimer's disease. Rev Neurosci. 2006;17(5):497-523. PubMed.
Stellwagen D, Malenka RC. Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. PubMed.
Pickering M, Cumiskey D, O'Connor JJ. Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005 Sep;90(5):663-70. PubMed.
Turrigiano GG, Leslie KR, Desai NS, Rutherford LC, Nelson SB. Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998 Feb 26;391(6670):892-6. PubMed.
Watt AJ, van Rossum MC, MacLeod KM, Nelson SB, Turrigiano GG. Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Neuron. 2000 Jun;26(3):659-70. PubMed.
Rosenberg PB. Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry. 2005 Dec;17(6):503-14. PubMed.
Rosenberg PB. Editorial: cytokine inhibition for treatment of Alzheimer's disease. MedGenMed. 2006;8(2):24. PubMed.
Grundman M, Corey-Bloom J, Thal LJ. Perspectives in clinical Alzheimer's disease research and the development of antidementia drugs. J Neural Transm Suppl. 1998;53:255-75. PubMed.
Thal LJ. Anti-inflammatory drugs and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):449-50; discussion 451-3. PubMed.
Thal LJ. Therapeutics and mild cognitive impairment: current status and future directions. Alzheimer Dis Assoc Disord. 2003 Apr-Jun;17 Suppl 2:S69-71. PubMed.
View all comments by E TWalton's recent study of pyramidal neurons from the hippocampus of autopsy-confirmed AD patients found that all NFTs were associated with cytoplasmic aluminum. While the absorption of the metal by the NFTs may reduce inflammation and oxidation, NFT density ultimately killed neurons by enucleation (1). Formation of NFTs will also impede the flow of tau, building materials and chemicals through the axons as a number of authors have explored. Transport deficits take place early in AD. Clogging of axonal communication between the entorhinal cortex with its high aluminum level in AD, and the hippocampus could be one source of isolation of the hippocampus (2,3).
References:
Walton JR. Aluminum in hippocampal neurons from humans with Alzheimer's disease. Neurotoxicology. 2006 May;27(3):385-94. PubMed.
Singer SM, Chambers CB, Newfry GA, Norlund MA, Muma NA. Tau in aluminum-induced neurofibrillary tangles. Neurotoxicology. 1997;18(1):63-76. PubMed.
Andrási E, Páli N, Molnár Z, Kösel S. Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis. 2005 Aug;7(4):273-84. PubMed.
View all comments by Erik JanssonThe Jackson Lab
As of August 2014, we have not seen evidence of the phenotypic drift (later onset of symptoms) in the Jackson Laboratory colony as was reported by Dr. Virginia Lee's lab (Iba et al., 2013).
References:
Iba M, Guo JL, McBride JD, Zhang B, Trojanowski JQ, Lee VM. Synthetic tau fibrils mediate transmission of neurofibrillary tangles in a transgenic mouse model of Alzheimer's-like tauopathy. J Neurosci. 2013 Jan 16;33(3):1024-37. PubMed. Correction.
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