27 May 2011. In the brains of people with Alzheimer’s disease, misshapen neurons clog with organelles—ironically, the very ones in the autophagic-lysosomal system that normally help cells dispose of damaged organelles and protein waste. This abnormality seems to characterize AD, but not other neurodegenerative disorders. A study in this week’s Journal of Neuroscience offers a potential explanation for it. In cell biology studies of mouse cortical neurons, researchers at New York University School of Medicine show that inhibiting proteolysis in lysosomes selectively slows the shuttling of autophagic and lysosomal organelles along neuron projections. “Coincidentally, that reproduces the characteristic axonal dystrophy in AD,” said senior investigator Ralph Nixon of the NYU-affiliated Nathan Kline Institute for Psychiatric Research, Orangeburg, in an interview with ARF. Though axonal transport dysfunction characterizes many neurodegenerative diseases (see Roy et al., 2005), the current study, “to my knowledge, may suggest the first real mechanism to explain the highly selective transport deficits that are evident in AD brain.”
Research dating back 20 years hinted that the lysosomal system goes awry in AD. In postmortem patient brains, neurons swell with lysosomes, and lysosomal enzymes lurk within amyloid plaques (see Cataldo et al., 1990; Cataldo et al., 1991; Nixon et al., 1992). Ultrastructural studies confirmed that neurons in AD brains selectively accumulate autophagosomes and other degradative vesicles (Nixon et al., 2005), suggesting that the problem was not a global disruption of axonal transport, but rather a more specific defect. Then, Nixon’s group proposed a novel role for presenilin (PS) in lysosomal function, and that familial AD-linked PS mutations disrupt that function (ARF related news story on Lee et al., 2010). “That nailed it for us,” Nixon said, “at least the notion that a primary lysosomal problem could be a meaningful part of AD pathogenesis.”
The NYU researchers launched several studies to home in on the lysosomal pathway. A genetic approach to boosting autophagy was able to relieve these lysosomal defects and lessen pathology and cognitive decline in an AD mouse model (see ARF related news story on Yang et al., 2011). The other, reported in the current paper, addressed the converse question—namely, whether inducing a primary lysosomal disturbance can bring on AD-like pathogenesis.
To find out, first author Sooyeon Lee, who is now at the University of Florida in Gainesville, tracked the movement of autophagic organelles within primary cortical neurons from wild-type mice. With time-lapse imaging and fluorescent indicators, she watched various degradative compartments and organelles move along neuronal projections, each with characteristic patterns. Autophagosomes trudged steadily in the retrograde direction, while late endosomes and lysosomes scooted more quickly and went in both directions, likely speeding their fusion with autophagosomes, the authors note. Mitochondria also traveled in both directions, but paused frequently.
In cells treated with pharmacologic agents that disrupt lysosomal proteolysis, the researchers saw autolysosomes, late endosomes, and lysosomes moving more slowly and collecting in bulges on dystrophic projections. However, mitochondria and other organelles maintained their normal transit patterns, suggesting the treatment did not hamper axonal transport in general.
After the drug-treated cells were restored to living in regular medium, endolysosomal vesicles picked up speed along axons and the swollen regions shrank, indicating a return to health. “When you see dystrophy, it doesn’t necessarily mean the neuron is dying,” Nixon said. “This could well be some sort of interim compensatory reaction. The dystrophy is quite reversible, and not a phenomenon of neurodegeneration, at least in the early stages.”
However, given that the neurons in the current study came from animals free of plaques and tangles—standard hallmarks of Alzheimer's pathology—some scientists question the relevance of the findings to AD. “It is not clear that this pattern of axonal dystrophy is truly AD-like,” suggested Scott Brady of the University of Illinois at Chicago in an e-mail to ARF. “Any number of treatments can produce this phenotype.”
Nixon said his lab is moving the studies in vivo—giving wild-type mice brain infusions of lysosomal protease inhibitors to see if this reproduces the pathology seen in cultured neurons and has functional ramifications that resemble AD. The researchers are also working to define the mechanism by which a primary lysosomal problem could stymie transport of degradative organelles. They think it may have something to do with molecular motors because they saw, in the present study, less of the motor protein dynein attached to degradative vesicles in neurons with blocked lysosomal proteolysis.—Esther Landhuis.
Lee S, Sato Y, Nixon RA. Lysosomal proteolysis inhibition selectively disrupts axonal transport of degradative organelles and causes an Alzheimer’s-like axonal dystrophy. J Neurosci. 25 May 2011;31(21):7817-7830. Abstract