Feeling good on the outside often helps us feel good on the inside. Could the same be true for neurons? In today’s issue of the journal Neuron, Frank LaFerla and colleagues at the University of California, Irvine, report that antibodies to amyloid-β not only clear up extracellular amyloid plaques, but they promote clearance of intracellular neurofibrillary tangles too. The results should be music to the ears of vaccine developers, and may boost the flagging amyloid cascade hypothesis.
First author Salvatore Oddo and colleagues discovered the effect when they passively immunized triple transgenic (3xTg-AD) mice with antibodies to Aβ. Developed by LaFerla and colleagues, 3xTg-AD mice harbor presenilin, APP, and tau mutants, and recapitulate the two classic hallmarks of Alzheimer’s disease (AD), amyloid plaques and neurofibrillary tangles (see Oddo et al., 2003 and ARF related news story for descriptions of this mouse model).
Oddo immunized the animals by injecting antibodies into one side of the hippocampus (antibodies used were commercially available monoclonals to human Aβ). Examining the mice seven days later, the authors found that the ipsilateral side showed a marked reduction in the number of plaques, as judged by immunoreactivity and thioflavin S staining. In contrast, there was no improvement on the side of the hippocampus that received no antibody.
Plaque clearance by passive immunization is not big news in and of itself (see, for example, a recent roundup of various vaccination strategies and their outcomes), but what is remarkable about this study is that the authors found that intracellular aggregates of tau, the major component of neurofibrillary tangles, had also disappeared. This loss was also restricted to the treated side of the hippocampus.
The reduction of both Aβ and tau aggregates suggests a “direct relationship between the development and expression of these two neuropathological lesions,” write the authors. And to confirm this relationship, Oddo and colleagues looked at the time course of events following immunization. If their hypothesized relationship held true, then Aβ clearance should precede tau clearance, and indeed, this is what the authors found. Three days after immunization, only the amyloid plaques had cleared; the tau aggregates did not begin to disappear until two days later.
How does passive immunization with anti-Aβ lead to clearance of intracellular tau? Some clues may come from the clearance of Aβ itself. Oddo and colleagues found that it is not only extracellular Aβ but also the intracellular form that is cleared—perhaps because it diffuses out of neurons to maintain an intra/extracellular equilibrium. Could reducing the amount of intracellular Aβ help prevent tau aggregates, and how?
LaFerla and colleagues explored the possibility that the proteasome may be involved because impairment of this crucial protein disposal has been implicated in AD (see the ARF milestone paper by Keller et al., 2000) and it has been reported that Aβ may inhibit subunits of the complex (see Gregori et al., 1997). When the authors injected mice with Aβ antibody and the proteasome inhibitor epoxomicin, amyloid plaque clearance occurred as before, but clearance of tau was almost nonexistent. This supports the theory that intracellular Aβ may inhibit the proteasome and prevent degradation of unwanted tau.
These results give a big boost to the vaccine development camp. One of the major criticisms of Aβ vaccination therapy is that it just tackles one of the effects of AD (extracellular plaques) but not the cause (internal neuronal dysfunction). But this paper suggests that a vaccination approach may do both. It also lends support to the amyloid cascade hypothesis. “These findings…provide strong supporting evidence for the amyloid cascade hypothesis, which stipulates the Aβ accumulation triggers the onset of AD and that tau hyperphosphorylation, subsequent neurofibrillary tangle formation, and cell death are downstream consequences of Aβ aggregation,” write the authors.
Whether passive immunization against Aβ would have such dramatic effects in humans remains to be seen. But a few caveats are worth keeping in mind. The authors found that tau clearance only occurs if the protein hasn’t become hyperphosphorylated. “Because the clearance of the tau pathology is dependent on its phosphorylation state, it indicates that Aβ immunotherapy late during the disease course may still effectively clear amyloid plaques, although it will be insufficient to impact the neurofibrillary pathology,” La Ferla and colleagues write. For this reason they suggest that it will be essential to test tau antibodies, particularly those recognizing phosphorylated forms, for the ability to clear tau.
Also, as with most passive immunizations, the effects are not permanent (see also comment below by Dave Morgan). About 30 days after vaccination, aggregates reemerge. Interestingly enough, it is the Aβ plaques that form first, followed by tau aggregates. Now there’s some good evidence for the cascade hypothesis.—Tom Fagan
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- 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.
- Keller JN, Hanni KB, Markesbery WR. Impaired proteasome function in Alzheimer's disease. J Neurochem. 2000 Jul;75(1):436-9. PubMed.
- Gregori L, Hainfeld JF, Simon MN, Goldgaber D. Binding of amyloid beta protein to the 20 S proteasome. J Biol Chem. 1997 Jan 3;272(1):58-62. PubMed.
- Oddo S, Billings L, Kesslak JP, Cribbs DH, Laferla FM. Abeta immunotherapy leads to clearance of early, but not late, hyperphosphorylated tau aggregates via the proteasome. Neuron. 2004 Aug 5;43(3):321-32. PubMed.