. 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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  1. 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within minutes, in verbal fluency, affect, and attention following perispinal etanercept [3,13] (some results as yet unpublished) are perhaps best explained by the known effects of TNFα on synaptic transmission and synaptic scaling [14-18].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.

    View all comments by E T
  2. Walton'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).

    View all comments by Erik Jansson