The Ups and Downs of Aβ: Synaptic Activity Yields Mixed Results

Do we use it or lose it, or use it and lose it? If synaptic activity spurs Aβ production, why do education, environmental stimulation, and socialization all protect against AD? A possible explanation comes from Gunnar Gouras and colleagues of Weill Medical College of Cornell University, New York, with data that suggest a more positive effect of synaptic activity on Aβ dynamics. Writing in the August 5 Journal of Neuroscience, they report that even while synaptic activity boosts extracellular Aβ levels, it reduces intraneuronal Aβ, and that reduction is enough to ameliorate synaptic toxicity. The results support the idea that where Aβ is concerned, neuronal activity benefits neurons. The work also bolsters the theory that intraneuronal Aβ can bring down synapses, and paints a more complex picture of activity-induced Aβ regulation, which includes the shuttling of amyloid precursor protein (APP) to synapses, and neprilysin-mediated Aβ degradation.

Previous work showed that synaptic activity drives Aβ secretion (see ARF related news story on Kamenetz et al., 2003 and ARF related news story on Cirrito et al., 2005), and accounts for the majority of APP endocytosis, processing, and Aβ production in the brain (see ARF related news story on Cirrito et al., 2008). Early Aβ deposition also seems to occur preferentially in places of high neuronal activity (see ARF related news story on Buckner et al., 2009). However, the new work suggests that synaptic activity has another side, too, where it reduces the intraneuronal pool of Aβ and normalizes synapses, Gouras told ARF. “This goes against the idea that the activity-dependent secretion of Aβ is a bad thing and suggests there is a balance.”

In the study, first author Davide Tampellini and colleagues focused on the effects synaptic activity has not on extracellular, but on the intraneuronal pool of Aβ, which is increasingly viewed by Gouras and others as critical to Aβ toxicity. The researchers activated cultured primary neurons from mutant APP-overexpressing Tg2576 mice with a chemical cocktail that mimics the stimulus for long-term potentiation, and measured a 38 percent decrease in levels of intraneuronal Aβ40 and Aβ42 by ELISA, along with the expected increase in secreted Aβ. They also saw a reduction in immunofluorescent Aβ in dendrites. The same reduction was seen in potassium chloride (KCl)-activated hippocampal slices from another mutant APP transgenic mouse, Tg19959 (see ARF related news story on Li et al., 2004). In the latter, they saw an increase in Aβ levels in inactive neurons in the whisker barrel cortex after chronic understimulation caused by removal of the whisker bulb afferents. This suggests that synaptic activity negatively regulates intraneuronal Aβ in vivo.

With extracellular Aβ going up, and intracellular Aβ going down, the researchers asked whether, on balance, synaptic activity would help or harm the neurons. They looked at the impact of activation on synapse structure by staining neurons in culture for the synaptic protein PSD-95. The protein is normally decreased in Tg2576 neurons compared to wild-type, but after activation the researchers found levels rebounded to wild-type, whereas activation of wild-type neurons had no effect. This suggests that synaptic activity has an overall protective effect, and that the positive effects of reducing intraneuronal Aβ override the potential negative effects of extracellular Aβ release.

The connection between intracellular and extracellular Aβ is complex: It has been established that extracellular Aβ can trigger the production of new intracellular Aβ, and that this production is required for synaptic downregulation (see Yang et al., 1999 and ARF related news story). Outside-in effects appeared important for the synaptic effects of exogenous Aβ in this system as well. Using γ-secretase inhibitors or APP knockout mice, the researchers showed that new processing and production of intraneuronal Aβ are required for externally added Aβ to bring down PSD-95 levels.

In other experiments, the researchers revealed more details of the effects of synaptic activity on the natural history of Aβ. Using live cell imaging, they watched APP while applying the activating solution to cultured cells. Gouras said that within 10 to 20 seconds, they could see APP-carrying vesicles that were being transported away from synapses actually turn and go back. Cell labeling experiments showed that APP increased on the surface of neurons after activation, except in synapses. This work supports the model that upon activation, APP travels to synapses, where it is then internalized, and processed. The destruction of Aβ, on the other hand, depended on neprilysin. Gouras said they focused on that protease because it is the most efficient degrader of Aβ, and it is increased in the brains of animals after environmental enrichment (see ARF related news story on Lazarov et al. 2005). Using a neprilysin inhibitor or neprilysin knockout mice, they showed that loss of the protease prevented the reduction in Aβ42 by synaptic activity.

When it comes to Aβ and synaptic activity, Gouras concludes, “We tend to say something is good or bad, but that’s too simple. Synaptic activity has a good side. Our results suggest it is good to get rid of intracellular Aβ, and not a problem to get out some extracellular Aβ.” However, he says, “For some reason people get more vulnerable with aging, and very active areas are a setup for AD to start.”

In the same vein, he says, “We have to be careful saying extracellular Aβ is bad,” pointing to the recent work that in patients with severe head trauma, extracellular Aβ is very low, and goes up when they begin to improve their cognitive function (see ARF related news story on Brody et al. 2008). In addition, there is evidence that very low concentrations of extracellular Aβ might play a physiological role in learning and memory (see ARF related news story on Puzzo et al., 2008), although Gouras notes this is controversial.—Pat McCaffrey

Comments

  1. This paper by Tampellini and colleagues is an interesting account of amyloid precursor protein (APP) trafficking and amyloid beta (Aβ) metabolism as a result of synaptic activity. Using glycine chemical long-term potentiation (LTP) and direct depolarization with potassium, they show that intracellular Aβ levels decrease. Previous work by our group and Roberto Malinow’s group has demonstrated that synaptic activity induces Aβ generation and release from neurons (Cirrito et al., 2008; Kamenetz et al., 2003). Tampellini and colleagues’ data is entirely consistent with this model; synaptic activity increases Aβ release thereby reducing intracellular Aβ. Interestingly, Davide shows that synaptic activity also enhances neprilysin-mediated degradation of intracellular Aβ. This appears to be Aβ42-specific since intracellular Aβ40 levels still decrease in the presence of thiorphan, an inhibitor of neprilysin. This suggests that newly generated Aβ can proceed down at least two pathways: release or degradation. The mechanisms that decide Aβ’s fate are unclear and how those mechanisms would differentially affect Aβ sub-species is unknown. Additionally, the percentage of Aβ that is released as opposed to degraded intracellularly remains an open question. Like any good study, Tampellini and colleagues generate more questions than are answered.

    It appears that synaptic activity can differentially affect Aβ within distinct brain compartments. Our previous work has demonstrated that synaptic vesicle exocytosis rapidly increases extracellular Aβ levels in vivo (Cirrito et al., 2005). This is a presynaptic event. Tampellini now shows that synaptic activity also affects intracellular Aβ degradation to some extent. Additionally, activation of postsynaptic receptors can also lead to signaling pathways that alter APP processing and Aβ levels. Over 15 years ago it was shown that M1 muscarinic acetylcholine receptors can reduce Aβ levels (Nitsch et al., 1992) in a PKC-dependent pathway. More recently it was shown that activation of NMDA receptors can also increase α-secretase cleavage thereby reducing Aβ generation (Hoey et al., 2009). The interplay of each of these synapse-related mechanisms will determine overall brain Aβ levels. How all of these mechanisms collectively contribute to Aβ toxicity in the setting of Alzheimer disease must still be determined.

    References:

    Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.

    Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.

    Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.

    Nitsch RM, Slack BE, Wurtman RJ, Growdon JH. Release of Alzheimer amyloid precursor derivatives stimulated by activation of muscarinic acetylcholine receptors. Science. 1992 Oct 9;258(5080):304-7. PubMed.

    Hoey SE, Williams RJ, Perkinton MS. Synaptic NMDA receptor activation stimulates alpha-secretase amyloid precursor protein processing and inhibits amyloid-beta production. J Neurosci. 2009 Apr 8;29(14):4442-60. PubMed.

    View all comments by John Cirrito

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References

News Citations

  1. Synapses Sizzle in Limelight of Symposium Preceding Neuroscience Conference, Orlando: Day 2
  2. Paper Alert: Synaptic Activity Increases Aβ Release
  3. Link Between Synaptic Activity, Aβ Processing Revealed
  4. Cortical Hubs Found Capped With Amyloid
  5. Aβ Production Linked to Oxidative Stress
  6. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  7. Sorrento: More Fun, Less Amyloid for Transgenic Mice
  8. Soluble Aβ—Bane or Boon? Real-time Data in Humans Yield New Insight
  9. Aβ Boosts Memory; Mint/X11 Proteins Boost Aβ?

Paper Citations

  1. Kamenetz F, Tomita T, Hsieh H, Seabrook G, Borchelt D, Iwatsubo T, Sisodia S, Malinow R. APP processing and synaptic function. Neuron. 2003 Mar 27;37(6):925-37. PubMed.
  2. Cirrito JR, Yamada KA, Finn MB, Sloviter RS, Bales KR, May PC, Schoepp DD, Paul SM, Mennerick S, Holtzman DM. Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron. 2005 Dec 22;48(6):913-22. PubMed.
  3. Cirrito JR, Kang JE, Lee J, Stewart FR, Verges DK, Silverio LM, Bu G, Mennerick S, Holtzman DM. Endocytosis is required for synaptic activity-dependent release of amyloid-beta in vivo. Neuron. 2008 Apr 10;58(1):42-51. PubMed.
  4. Buckner RL, Sepulcre J, Talukdar T, Krienen FM, Liu H, Hedden T, Andrews-Hanna JR, Sperling RA, Johnson KA. Cortical hubs revealed by intrinsic functional connectivity: mapping, assessment of stability, and relation to Alzheimer's disease. J Neurosci. 2009 Feb 11;29(6):1860-73. PubMed.
  5. Li F, Calingasan NY, Yu F, Mauck WM, Toidze M, Almeida CG, Takahashi RH, Carlson GA, Flint Beal M, Lin MT, Gouras GK. Increased plaque burden in brains of APP mutant MnSOD heterozygous knockout mice. J Neurochem. 2004 Jun;89(5):1308-12. PubMed.
  6. Yang AJ, Chandswangbhuvana D, Shu T, Henschen A, Glabe CG. Intracellular accumulation of insoluble, newly synthesized abetan-42 in amyloid precursor protein-transfected cells that have been treated with Abeta1-42. J Biol Chem. 1999 Jul 16;274(29):20650-6. PubMed.
  7. Lazarov O, Robinson J, Tang YP, Hairston IS, Korade-Mirnics Z, Lee VM, Hersh LB, Sapolsky RM, Mirnics K, Sisodia SS. Environmental enrichment reduces Abeta levels and amyloid deposition in transgenic mice. Cell. 2005 Mar 11;120(5):701-13. PubMed.
  8. Brody DL, Magnoni S, Schwetye KE, Spinner ML, Esparza TJ, Stocchetti N, Zipfel GJ, Holtzman DM. Amyloid-beta dynamics correlate with neurological status in the injured human brain. Science. 2008 Aug 29;321(5893):1221-4. PubMed.
  9. Puzzo D, Privitera L, Leznik E, Fà M, Staniszewski A, Palmeri A, Arancio O. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci. 2008 Dec 31;28(53):14537-45. PubMed.

Further Reading

Primary Papers

  1. Tampellini D, Rahman N, Gallo EF, Huang Z, Dumont M, Capetillo-Zarate E, Ma T, Zheng R, Lu B, Nanus DM, Lin MT, Gouras GK. Synaptic activity reduces intraneuronal Abeta, promotes APP transport to synapses, and protects against Abeta-related synaptic alterations. J Neurosci. 2009 Aug 5;29(31):9704-13. PubMed.

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