While amyloid-β (Aβ) seems to have the majority vote for the protein culprit in Alzheimer disease (AD), the election is not quite as clear regarding which Aβ assembly state produces AD’s cognitively crippling characteristics. An increasing number of reports show that globular, soluble Aβ oligomers rather than Aβ plaques containing insoluble Aβ fibrils are to blame for the cognitive deficits (see ARF related news story and ARF news story). Using transgenic mouse models to manipulate Aβ assembly states, Lennart Mucke at the Gladstone Institutes/University of California and coauthors demonstrate that speeding up Aβ fibrillization into plaques diminishes Aβ oligomers and protects against cognitive deficits in AD mouse models. The report appears in the August 17 Journal of Biological Chemistry.
Taking advantage of the E22G Arctic mutation that accelerates Aβ aggregation into protofibrils and fibrils, the researchers studied the balance between fibrillar and nonfibrillar (or oligomeric) Aβ assembly states. First author Irene Cheng and coauthors show—for what they believe is the first time—three-dimensional morphological and quantitative characteristics of Aβ oligomers isolated directly from brain tissue, using atomic force microscopy (see ARF related news story). By analyzing synthetic Aβ peptides, the researchers confirmed that the Arctic mutation accelerates fibril formation and demonstrated that this effect actually lowers the relative abundance of Aβ oligomers.
Then the researchers evaluated how the Arctic mutation’s promotion of fibrillization altered Aβ assembly and cognition in three different mouse models, each engineered to have elevated levels of Aβ42 but with varying speeds of turning Aβ monomers into mature plaques. At 3-4 months, J20 mice had no plaques, ARC48 had lots of plaques, and ARC6 mice had few plaques. Oligomer levels were highest in J20 mice, a little lower in ARC48 mice, and undetectable in ARC6 mice.
Behavioral analyses using cued and spatial versions of the Morris water maze task showed a striking dissociation between cognitive deficits and Aβ plaques. “We find that cognitive deficits correlate best with oligomeric Aβ,” said Mucke of a pattern of results that is consistent with what coauthor Karen Ashe described last year (see ARF related news story) in which Aβ oligomers infused directly into the brain temporarily impaired memory. Now Mucke and colleagues extend those findings by demonstrating oligomer dependence of memory deficits across different mouse lines and normal memory in the ARC6 line, which had plaques but no oligomers.
The cognitive impairment associated with increased Aβ oligomers, regardless of plaques, indicates that shifting around Aβ assembly states can alter different aspects of the disease. The ARC6 mice showed quick transition of Aβ from monomers to plaques with decreased time spent in the oligomer state. “Even though they have more plaques, they have better memory,” Mucke said. “What matters here is the critical pool of oligomeric species.”
The results not only call into question whether plaque-detecting diagnostics (see ARF related news story) will correlate well with cognitive impairments, but also caution against pharmaceuticals that might inadvertently increase Aβ oligomers. “This paper may warn people in drug development that preventing fibril formation could be dangerous if it is associated with increasing oligomers,” said Mucke. “We’re highlighting how shifting Aβ quickly into fibrils could diminish the pool of pathogenic oligomers.”—Molly McElroy
Molly McElroy is a freelance writer based in Melbourne, Florida.
- 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.