Another round of cat-and-mouse between scientists and the surreptitious cause of Alzheimer's pathogenesis shows intracellular Aβ lesions lead to age-dependent neurodegeneration and motor impairment in rodents.
Matthias Staufenbiel of the Novartis Institutes for Biomedical Research in Basel, Switzerland, and colleagues created genetically modified mice that produce abundant levels of Aβ40 and/or Aβ42 within their neurons. The location of the transgenic peptides differentiates the work from previous studies, which described mice that secrete the partial APP peptides into the neuronal milieu (McGowan et al., 2005). Although the previously reported mice develop Aβ deposits, they do not show signs of overt toxicity, and so speak to a possibility that intraneuronal Aβ aggregates are among the saboteurs in AD. The new study attempts to explore this possibility.
The study injects new data into an ongoing scientific debate about the role of intraneuronal Aβ, which has recently moved to a focus on the technical challenges of distinguishing Aβ species from their parental precursor, APP (see ARF Webinar).
By linking the partial APP peptides to an N-terminal signal sequence, the researchers forced production of Aβ40 and Aβ42 within the endoplasmic reticulum. The molecular engineering places the peptides in arguably a more natural location within the cell—inside the lumen of the ER and other components of the intracellular membrane system. However, as with other Aβ transgenic mouse studies, the consequences of removing the Aβ peptides from APP are unknown and potentially far reaching. "When you take Aβ out of the context of APP processing, I don't think you really know how relevant the effects are for the disease," said Lars Nilsson of Oslo University in Norway. "The digestion and release of Aβ will change dramatically both in terms of subcellular location and mechanism, which could affect the aggregation process," he said.
Even so, the novel approach to creating Aβ transgenic models can teach us about the basic biology of these proteins, said Nilsson. The authors used histochemical analysis to examine brain sections of mice that expressed either Aβ40 or Aβ42. The latter strain showed significant aggregates and functional problems, while the Aβ40 strain did not. The combined transgenic exhibited intermediate levels of aggregation and pathologies, supporting the possibility that Aβ40 destabilizes the aggregation of Aβ42.
The intraneuronal aggregates were not plaques. Instead, the authors saw Aβ-positive threads within dendrites, dot-like granules in nerve cell bodies, and grain-like structures throughout the gray matter of the brain. Although these strains do not replicate the pathology of AD, the Aβ42 strain does have neurodegeneration and white matter atrophy within the hippocampus and other regions, as well as motor defects, the authors report. The functional impairments evolve over time as the mice age.
While the paper directly demonstrates that Aβ42 aggregates inside neurons cause neuronal death even in young mice, some other scientists express skepticism that the study settles the role of intraneuronal Aβ in AD.
"Direct overexpression of intracellular Aβ1-40 and Aβ1-42 in mice is extremely artificial," wrote Virginia Lee of the University of Pennsylvania School of Medicine in Philadelphia in an e-mail to Alzforum. In AD, Aβ peptides are generated from the proteolytic processing of APP and the majority of the cut materials are secreted—quite a different molecular journey than found in the new transgenic mice.
There is no animal model that recapitulates all or even most of the features of AD. But animal models do allow researchers to test connections between molecular and cellular features of APP and its Aβ offshoots on the one hand, and downstream effects such as white matter loss on the other.
"You can sometimes learn a lot from simply playing around with things and seeing what happens," said Nilsson.—Susan Young
Susan Young is a science writer in Washington, D.C.
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