Stress and Aβ—The Apoptosis Connection

See other stress stories 1 and 3.

Physical and psychological stress can have long-lasting effects on the brain and even put people at risk for dementia. New research suggests that both forms of stress can cause an increase in production of Aβ, though perhaps in slightly different ways. A companion story described work from David Holtzman and colleagues at Washington University, St. Louis, who reported in this week’s PNAS that psychological stress in mice enhances neuronal Aβ production. In the June 7 Neuron, Rudy Tanzi and colleagues at Massachusetts General Hospital reported that physical stress, in the form of ischemia, can elevate Aβ by restricting degradation of BACE, the enzyme that catalyzes the first of two proteolytic snips that release the peptide from its precursor. The finding may help explain why stroke and other trauma may predispose people to subsequent Alzheimer disease.

In scrutinizing BACE, researchers have learned that it is elevated in AD (see ARF related news story) and also following ischemia and traumatic brain injury, suggesting that BACE responds to trauma. Exactly how BACE and trauma are related is not clear, however. Now first author Giuseppina Tesco and colleagues report that caspase-3, a key player in apoptosis, or programmed cell death, may be the link.

Apoptosis is implicated in AD pathology (see ARF related Live Discussion). It has been linked to increased Aβ production and it was this relationship that Tesco and colleagues set out to investigate. When the scientists induced apoptosis in neuroblastoma cells, they detected an increase in Aβ and also in C99, the C-terminal portion of APP left over after BACE cleavage. They did not detect caspase-mediated cleavage of APP itself, though they did use antibodies specifically designed to test this possibility. The finding suggests that during apoptosis, caspases do not attack APP directly, but that they somehow increase BACE levels. In fact, Tesco and colleagues found that BACE protein levels were elevated up to ninefold in cells following apoptosis and that it became more stable. The findings suggest that while apoptosis sets off a proteolytic cascade that devours many cellular proteins, it somehow spares BACE.

BACE is normally targeted to the lysosome for degradation. This fate seems to depend on a specific di-leucine motif in the protein (DXXLL), because when those leucines are mutated to alanines, BACE accumulates at the cell membrane. In other proteins the di-leucine motif beckons proteins called GGAs (Golgi-localized γ-ear-containing ARF binding proteins), which are known for shepherding acid hydrolase enzymes through the trans-Golgi network toward lysosomes. Additional work suggests that GGAs direct endosomal proteins, such as epidermal growth factor receptors, to the lysosome, as well. In fact, recently researchers found that knocking down GGA3 causes a buildup of BACE in the endosomal compartment (see He et al., 2004).

To test if GGA-mediated trafficking of BACE might go awry during apoptosis, Tesco and colleagues measured levels of GGA3. They found that the protein was degraded by none other than caspase-3 following induction of apoptosis. Furthermore, when the authors used RNAi to knock down GGA3 in H4 cells expressing APP, they found that BACE was significantly elevated (fourfold in cells expressing APP with Swedish mutation and sevenfold in cells expressing APP751). Concomitantly, there was a significant increase in Aβ40 (1.5-fold in APPSw cells and over twofold in APP751 cells).

The findings suggest that any trauma that causes apoptosis may also attenuate BACE degradation and ultimately lead to increased Aβ production. In support of this idea the researchers looked for signs of apoptosis-mediated Aβ increases in a rat model of stroke. They found that cerebral ischemia caused degradation of GGA3 and an increase in BACE in the affected but not the opposite control side of the brain. They also found that GGA3 levels are low in postmortem samples of temporal cortex from AD patients and that levels of GGA3 and BACE are inversely proportional in those samples—less GGA3, more BACE. “In summary, our studies suggest that elevated BACE protein levels found in AD patients and animal models of acute brain injury, including ischemia and acute head trauma, may be at least partly due to stabilization and impaired degradation of BACE,” write the authors.

Together, the findings of Holtzman and colleagues (see ARF related news story) and now Tanzi and colleagues paint a picture whereby either psychological or physical stress can lead to an increase in Aβ production, putting people at elevated risk for developing AD. To what extent such stress contributes to the incidence of late-onset AD is unclear.—Tom Fagan

Comments

  1. Well done!

    View all comments by DC Kerr

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References

News Citations

  1. Stress and Aβ—A Fluid Connection in Mice
  2. Stress and AD—The Cognition Connection
  3. Follow the BACE to Higher Aβ Levels

Paper Citations

  1. He X, Li F, Chang WP, Tang J. GGA proteins mediate the recycling pathway of memapsin 2 (BACE). J Biol Chem. 2005 Mar 25;280(12):11696-703. PubMed.

Other Citations

  1. ARF related Live Discussion

Further Reading

Primary Papers

  1. Tesco G, Koh YH, Kang EL, Cameron AN, Das S, Sena-Esteves M, Hiltunen M, Yang SH, Zhong Z, Shen Y, Simpkins JW, Tanzi RE. Depletion of GGA3 stabilizes BACE and enhances beta-secretase activity. Neuron. 2007 Jun 7;54(5):721-37. PubMed.

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