The toxicity of neurofibrillary tangles has been hotly debated even though they are a hallmark of many neurodegenerative diseases, including Pick disease, frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), and Alzheimer disease (AD). Some recent studies suggest that, as with amyloid-β and other “sticky” proteins that form aggregates, fibrillar tau is not the cause of toxicity and might even be relatively protective. That view draws in-vivo support from recent work from Virginia Lee’s lab at the University of Pennsylvania, Philadelphia. In yesterday’s Neuron, Lee and colleagues report that in a mouse tauopathy model, various pathologies, including synapse loss and activated microglia, are apparent 3 months before the appearance of neurofibrillary tangles (NFTs). Furthermore, they show that much of the pathology can be prevented by giving the animals an immunosuppressant. The findings suggest that an aggressive immune response may be one of the earliest and detrimental consequences of tau mutations.

The mice in question express a mutant human tau that is responsible for an early-onset and particularly aggressive form of FTDP-17 (see Sperfeld et al., 1999 and Bugiani et al., 1999). First author Yasumasa Yoshiyama and colleagues engineered mice to express the P301S tau variant under the control of the mouse prion promoter. This PS19 transgenic strain, with fivefold higher expression of the transgene than endogenous mouse tau, had neurologic symptoms from age 3 months that rapidly developed into muscle weakness and paralysis. By 12 months, about 80 percent of the animals died. In contrast, another strain expressing wild-type human tau at the same level appeared normal until at least 24 months.

Yoshiyama and colleagues found that while levels of insoluble tau in brain extracts of PS19 animals progressively increased from about 1 month after birth, no NFTs were apparent at 3 months, when the animals already showed signs of neurologic damage. In fact, between 1 and 3 months, synaptic pathology already manifested itself in the CA3 layer of the hippocampus, as determined by loss of the synaptic markers synaptophysin and α-synuclein. Also at 3 months, levels of calnexin, an endoplasmic reticulum-specific chaperone, were reduced in the dendrites (but not soma) of hippocampal neurons, suggesting impaired axonal transport. The authors also found tau spheroids, though no NFTs, in the synaptic compartment in these young mice, which the authors suggest could reflect detachment of mutant tau from the microtubules in axon terminals.

The immune response also seems to precede NFT formation. In 4-month-old mice, the scientists found activated microglia, as determined by elevated immunoreactivity to the microglial antigens HLA-D, CD11b, and HLA-DR. By using a radiotracer that binds these cells, the researchers quantitated the numbers of microglia in the hippocampus and entorhinal cortex and detected activation beginning at 3 months and intensifying over the next 6 months. Interleukin-1β and cyclooxygenase-2, other markers of inflammation, were also elevated by as early as 4 months.

To test the importance of the inflammatory response to the pathology of these animals, Yoshiyama and colleagues treated mice, beginning at 2 months of age, with the immunosuppressant FK506. This had a dramatic effect on pathology. Sixty percent of FK506-treated animals survived to 1 year compared to only 20 percent of untreated mice. Some of the treated mice had very little tau pathology and no overt hippocampal atrophy.

“We are excited by this paper. It shows that impaired function and loss of synapses in the hippocampus of a P301S tau transgenic mouse model of AD-like tau pathology is related to the activation of microglia and synaptic damage 3 months before tangles appear,” coauthor John Trojanowski, also at the University of Pennsylvania, wrote to Alzforum. “We think this explains the results of SantaCruz et al., 2005 (see ARF related news story). It also may explain why Frank LaFerla’s group observed cognitive impairments in triple-transgenic mice before the onset of tangles (see Billings et al., 2005),” Trojanowski added. Karen SantaCruz, working in Karen Hsiao-Ashe’s lab at the University of Minnesota Medical School in Minneapolis, had shown that suppressing tau expression alleviates symptoms and improves memory in a different mouse tauopathy model, despite the continued presence of NFTs, The triple-transgenic mice developed by LaFerla at the University of California, Irvine, have become a widely used model for teasing apart the relationships between amyloid-β and tau. LaFerla’s group showed that while early treatment of these animals with Aβ antibodies clears tau aggregates, that effect is lost if the treatment is done too late. In light of the present findings and SantaCruz’s work, perhaps the failure to clear tau tangles might be less pathologically relevant than eliminating soluble tau or the immune response.

On the latter score, Trojanowski suggested that “Abolishing the inflammation caused by the accumulation of tau might be a new therapy for neurodegenerative disorders like AD and related tauopathies. Our data suggest that microglia activation is linked to progression of tau-mediated neurodegeneration. It also suggests that FK506, or related ligands that bind FK-binding protein (FKBP) immunophilins, may have therapeutic benefit for tauopathy patients. This could occur via FK506-FKBP complexes that inhibit protein phosphatases 2B, so that nuclear factor of activated T cells (NFAT) remains phosphorylated, does not enter nuclei, and thereby leads to suppression of immune function, or it could occur by immunophilin-mediated chaperone or peptidylprolyl cis-trans isomerase activity, or other unknown mechanisms.”—Tom Fagan.

Reference:
Yoshiyama Y, Higuchi M, Zhang B, Huang S-M, Iwata N, Saido TC, Maeda J, Suhara T, Trojanowski JQ, Lee VM-Y. Synapse loss and microglial activation precede tangles in P301S tauopathy mouse model. Neuron. 2007 Feb 1;53:337-351. Abstract

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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.

    References:

    . 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.

    . TNF-alpha modulation for treatment of Alzheimer's disease: a 6-month pilot study. MedGenMed. 2006;8(2):25. PubMed.

    . Evidence for the involvement of TNF and NF-kappaB in hippocampal synaptic plasticity. Synapse. 2000 Feb;35(2):151-9. PubMed.

    . Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci. 2001 Aug;2(8):595-8. PubMed.

    . Control of synaptic strength by glial TNFalpha. Science. 2002 Mar 22;295(5563):2282-5. PubMed.

    . 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.

    . Alzheimer's disease: Abeta, tau and synaptic dysfunction. Trends Mol Med. 2005 Apr;11(4):170-6. PubMed.

    . Differential regulation of AMPA receptor and GABA receptor trafficking by tumor necrosis factor-alpha. J Neurosci. 2005 Mar 23;25(12):3219-28. PubMed.

    . Altered synaptic function in Alzheimer's disease. Eur J Pharmacol. 2006 Sep 1;545(1):11-21. PubMed.

    . Involvement of the nitric oxide pathway in synaptic dysfunction following amyloid elevation in Alzheimer's disease. Rev Neurosci. 2006;17(5):497-523. PubMed.

    . Synaptic scaling mediated by glial TNF-alpha. Nature. 2006 Apr 20;440(7087):1054-9. PubMed.

    . Actions of TNF-alpha on glutamatergic synaptic transmission in the central nervous system. Exp Physiol. 2005 Sep;90(5):663-70. PubMed.

    . Activity-dependent scaling of quantal amplitude in neocortical neurons. Nature. 1998 Feb 26;391(6670):892-6. PubMed.

    . Activity coregulates quantal AMPA and NMDA currents at neocortical synapses. Neuron. 2000 Jun;26(3):659-70. PubMed.

    . Clinical aspects of inflammation in Alzheimer's disease. Int Rev Psychiatry. 2005 Dec;17(6):503-14. PubMed.

    . Editorial: cytokine inhibition for treatment of Alzheimer's disease. MedGenMed. 2006;8(2):24. PubMed.

    . Perspectives in clinical Alzheimer's disease research and the development of antidementia drugs. J Neural Transm Suppl. 1998;53:255-75. PubMed.

    . Anti-inflammatory drugs and Alzheimer's disease. Neurobiol Aging. 2000 May-Jun;21(3):449-50; discussion 451-3. PubMed.

    . Therapeutics and mild cognitive impairment: current status and future directions. Alzheimer Dis Assoc Disord. 2003 Apr-Jun;17 Suppl 2:S69-71. PubMed.

  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).

    References:

    . Aluminum in hippocampal neurons from humans with Alzheimer's disease. Neurotoxicology. 2006 May;27(3):385-94. PubMed.

    . Tau in aluminum-induced neurofibrillary tangles. Neurotoxicology. 1997;18(1):63-76. PubMed.

    . Brain aluminum, magnesium and phosphorus contents of control and Alzheimer-diseased patients. J Alzheimers Dis. 2005 Aug;7(4):273-84. PubMed.

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References

News Citations

  1. No Toxicity in Tau’s Tangles?

Paper Citations

  1. . FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Ann Neurol. 1999 Nov;46(5):708-15. PubMed.
  2. . Frontotemporal dementia and corticobasal degeneration in a family with a P301S mutation in tau. J Neuropathol Exp Neurol. 1999 Jun;58(6):667-77. PubMed.
  3. . Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron. 2005 Mar 3;45(5):675-88. PubMed.
  4. . Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.

Further Reading

News

  1. No Toxicity in Tau’s Tangles?

Primary Papers

  1. . Synapse loss and microglial activation precede tangles in a P301S tauopathy mouse model. Neuron. 2007 Feb 1;53(3):337-51. PubMed.