17 August 2005. Studies in Drosophila have been exceedingly fruitful in teasing out physiological roles for the amyloid precursor protein (AβPP), parent to the amyloidogenic and toxic Aβ peptide. First, flies revealed that AβPP promotes synapse formation at the neuromuscular junction during development (see ARF related news story). Now, a new fly tale, this one from the labs of Bassem Hassan and Bart de Strooper in Leuven, Belgium, reveals another purpose for AβPP—this one in the CNS of adult animals, where, the authors find, AβPP promotes neurite outgrowth from fully mature neurons. Even more interesting is their observation that the Drosophila homolog of the precursor protein, APPL, is upregulated after brain injury, and seems to protect flies from death. Increased AβPP expression after injury could explain the link between brain trauma and Alzheimer disease in humans.
To study the two proteins in the fly brain, first author Maarten Leyssen and his coworkers chose a well-characterized model of arborization of the cells of the small lateral neurons ventral (sLNv). In a paper published online in the EMBO Journal on July 28, they show that this small group of four to five neurons, with their simple axonal pattern, is
ideal for the quantitation of axonal arborization in flies with targeted overexpression of APPL. While elevating APPL or human AβPP had no effect on the early development of these cells, it did induce a dose-dependent and extensive arborization in later developmental stages. Using this assay, the researchers expressed truncated and mutant forms of AβPP and established that arborization depended on an intact AβPP C-terminus and interaction with the Abl tyrosine kinase via the Dab scaffolding protein. In fact, expression of Abl kinase itself mimicked the effect of the Aβ precursor, showing that signaling via this pathway was necessary and sufficient for enhancing axonal arborization.
The type of axonal sprouting elicited by AβPP in flies is often seen in humans after brain injury, as is upregulation of AβPP expression (Murakami et al., 1998; Van den Heuvel et al., 1999). Is it possible, therefore, that APPL might serve a protective or regenerative function after a traumatic insult? To test this idea, the researchers developed a method for damaging flies using a needle-stick to the optic lobe. They showed that sustained, increased APPL expression occurred in the neurons around the site of injury. The induction of APPL was protective, since in the weeks after brain trauma, APPL-deficient flies showed significantly higher mortality than did wild-type. And just as in humans and mice, injury also activated the JNK signaling pathway. While this activation occurred independently of APPL upregulation, JNK activity was required to get the full effect of APP on arborization.
From this data, the authors suggest a model in which acute trauma produces increased APPL expression and simultaneous JNK activation. “JNK activity provides, via transcriptional activation of profilin and other cytoskeletal regulators, a permissive environment for remodeling of the actin cytoskeleton. Regulation of Abl signaling by APP ensures that these components are controlled functionally, resulting in an appropriate response to axonal damage,” they write. In their model, cleavage of AβPP by γ-secretase would put a halt to the restorative actions of the protein. This means the production of Aβ peptides could be nothing more than a side effect of upregulation of AβPP after stress or trauma, a view that might explain the observed relationship between AD and brain injury in people.—Pat McCaffrey.
Leyssen M, Ayaz D, Hebert SS, Reeve S, De Strooper B, Hassan BA. Amyloid precursor protein promotes post-developmental neurite arborization in the Drosophila brain. EMBO J. 2005 Aug 17;24(16):2944-2955. Epub 2005 Jul 28. Abstract