Paper
- Alzforum Recommends
Karlnoski RA, Rosenthal A, Kobayashi D, Pons J, Alamed J, Mercer M, Li Q, Gordon MN, Gottschall PE, Morgan D. Suppression of amyloid deposition leads to long-term reductions in Alzheimer's pathologies in Tg2576 mice. J Neurosci. 2009 Apr 15;29(15):4964-71. PubMed.
Recommends
Please login to recommend the paper.
Comments
Hertie Institute for clinical brains research
This is an intriguing and nice study. It tests the hypothesis whether Aβ plaques are in direct equilibrium with soluble Aβ. The results point to an accumulation model, and the given explanation for discrepancies with other well-reproducible observations is evident. It seems appropriate to speculate that plaque formation in vivo is a two-step process that involves a slow buildup of an Aβ seed (which contains oligomeric Aβ forms) and is followed by a rather fast and reversible (e.g., through immunotherapy) second step of growth to a histologically detectable and well-defined aggregate. Assuming that this is correct, it raises further questions that are extremely interesting:
1. Why is such a small seed stable enough not to be dissolved upon treatment with antibodies?
2. Why do at least some antibodies permanently block the conversion from a seed to a mature plaque (e.g., Meyer-Luehmann et al., 2006?
3. Is it possible to isolate such “core seeds” and will they still function as such when transferred to another host animal?
4. If so, what other components are contained in such a “core seed”?
References:
Meyer-Luehmann M, Coomaraswamy J, Bolmont T, Kaeser S, Schaefer C, Kilger E, Neuenschwander A, Abramowski D, Frey P, Jaton AL, Vigouret JM, Paganetti P, Walsh DM, Mathews PM, Ghiso J, Staufenbiel M, Walker LC, Jucker M. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science. 2006 Sep 22;313(5794):1781-4. PubMed.
This very important paper confirms the hypothesis that amyloid deposition is driven by accumulation of insoluble amyloid, probably following a seeding stage. It has been extensively shown previously by us and others that if you start an immunization paradigm early on in a mouse model, before deposition begins, you can prevent the deposition. Treatment is much less effective in clearing existing pathology. An important point observed in this paper is that even a window treatment at the right stage can delay future accumulation of pathology. It would be interesting to see, and is currently work in progress in our group, which stage is critical, i.e., which window treatment results in the most efficacious reduction of pathology: early, “seeding,” or later, “accumulation and plaque formation” stages.
University of Minnesota Medical School
To our knowledge, this study from David Morgan’s group provides the first published data showing that passive immunization during a restricted time window can provide a benefit that outlasts treatment for a considerable period of time (several months in mice). These data complement findings that Todd Golde, Pritam Das, and colleagues reported in Alzforum. Using the experimental γ-secretase inhibitor LY411575 to reduce Aβ production in Tg2576 during three different time windows (4M-7M, before plaques begin to accumulate; 7M-10M, when plaques are accumulating; 12M-15M, when plaques continue to accumulate at an accelerated rate), Golde’s group found that three months of drug treatment conferred lasting protection only when the drug was administered to the youngest age group, before plaques have accumulated.
Taken together with the findings of Golde’s group, Morgan’s results could have important therapeutic implications. Rapid plaque accumulation appears to follow a slow “seeding” phase, and a growing body of evidence suggests that plaque-reducing treatments are most effective when administered before or during the seeding phase, but that it is much more difficult to slow or reverse plaque accumulation once seeds are formed (Das et al., 2001; Jankowsky et al., 2005). The results of the study by Karlnoski et al. are consistent with this conclusion, but since these authors only looked at the effects of antibody treatment initiated relatively early (8M of age), we do not know the extent or duration of the efficacy of their treatment regimen if initiated later. In addition, plaque burden in the current study was quantified at only three time points, 8M, 14M, and 17M of age. With only three time points per group in this study, it is difficult to get a sense of the shape of the curves describing the kinetics of plaque accumulation (That is, is there a six-month shift to the right of the curves of plaque burden versus time, or do the curves change shape? The limited data suggest the latter.) Given a longer time after cessation of antibody treatment, would the anti-Aβ group catch up to the control group?
Perhaps the most important question yet to be answered is whether slowing plaque accumulation will also slow cognitive decline. The dissociation between amyloid burden and cognitive dysfunction in human AD and APP transgenic mice is well known; Aβ immunotherapy has been reported to reduce plaque burden without affecting cognitive function and vice versa (recently reviewed by Brody and Holtzman, 2008; Holmes et al., 2008). In APP transgenic mice, which we believe to be models of preclinical AD, soluble Aβ oligomers are associated with deficits in memory function (Lesné et al., 2006; Cheng et al., 2007; Meilandt et al., 2009). What is the effect of passive Aβ immunotherapy on soluble Aβ oligomers thought to mediate cognitive dysfunction? If Aβ immunotherapy also reduces levels of these soluble oligomers, when is treatment most effective? Is there a period during AD progression when plaques themselves mediate cognitive dysfunction, perhaps through local effects on neurite architecture? In AD patients, cognitive dysfunction might be mediated by different mechanisms at different stages of disease progression; while Aβ oligomers might initiate the disease, cognitive dysfunction at later stages might be mediated primarily by pathological species of tau, which are unaffected by Aβ immunotherapy.
The results from Morgan’s and Golde’s groups confirm that any particular therapy is likely to be effective during a restricted phase of disease progression, and they highlight the importance of understanding which molecules are toxic at different stages of AD.
References:
Brody DL, Holtzman DM. Active and passive immunotherapy for neurodegenerative disorders. Annu Rev Neurosci. 2008;31:175-93. PubMed.
Cheng IH, Scearce-Levie K, Legleiter J, Palop JJ, Gerstein H, Bien-Ly N, Puoliväli J, Lesné S, Ashe KH, Muchowski PJ, Mucke L. Accelerating amyloid-beta fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models. J Biol Chem. 2007 Aug 17;282(33):23818-28. PubMed.
Das P, Murphy MP, Younkin LH, Younkin SG, Golde TE. Reduced effectiveness of Abeta1-42 immunization in APP transgenic mice with significant amyloid deposition. Neurobiol Aging. 2001 Sep-Oct;22(5):721-7. PubMed.
Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008 Jul 19;372(9634):216-23. PubMed.
Jankowsky JL, Slunt HH, Gonzales V, Savonenko AV, Wen JC, Jenkins NA, Copeland NG, Younkin LH, Lester HA, Younkin SG, Borchelt DR. Persistent amyloidosis following suppression of Abeta production in a transgenic model of Alzheimer disease. PLoS Med. 2005 Dec;2(12):e355. Epub 2005 Nov 15 PubMed.
Lesné S, Koh MT, Kotilinek L, Kayed R, Glabe CG, Yang A, Gallagher M, Ashe KH. A specific amyloid-beta protein assembly in the brain impairs memory. Nature. 2006 Mar 16;440(7082):352-7. PubMed. RETRACTED
Meilandt WJ, Cisse M, Ho K, Wu T, Esposito LA, Scearce-Levie K, Cheng IH, Yu GQ, Mucke L. Neprilysin overexpression inhibits plaque formation but fails to reduce pathogenic Abeta oligomers and associated cognitive deficits in human amyloid precursor protein transgenic mice. J Neurosci. 2009 Feb 18;29(7):1977-86. PubMed.
Make a Comment
To make a comment you must login or register.