Both the paper by Bero and colleagues and the Alzforum news story make a tacit assumption concerning the relationship between synaptic activity and β amyloid-related synapse dysfunction: that reducing plaque by reducing activity-driven secretion of Aβ is good for the brain. But is this assumption true?

As Bero and colleagues are aware, we reported last year in the Journal of Neuroscience (Tampellini et al., 2010) that deafferented barrel cortex causes reduced plaques in AD transgenic mice, findings now confirmed by Bero and colleagues. We then asked whether this plaque reduction in the setting of decreased synaptic activity was good or bad for synapses. Decreased plaques suggested it may be good, as Holtzman and colleagues posit. But there was reason to consider that reduced synaptic activity might actually be harmful to synapses, since in 2009 we published also in the Journal of Neuroscience that synaptic activation protected cultured neurons of Tg2576 mice against synaptic damage, even though Aβ secretion was increased, most likely because synaptic activity caused...  Read more

Both the paper by Bero and colleagues and the Alzforum news story make a tacit assumption concerning the relationship between synaptic activity and β amyloid-related synapse dysfunction: that reducing plaque by reducing activity-driven secretion of Aβ is good for the brain. But is this assumption true?

As Bero and colleagues are aware, we reported last year in the Journal of Neuroscience (Tampellini et al., 2010) that deafferented barrel cortex causes reduced plaques in AD transgenic mice, findings now confirmed by Bero and colleagues. We then asked whether this plaque reduction in the setting of decreased synaptic activity was good or bad for synapses. Decreased plaques suggested it may be good, as Holtzman and colleagues posit. But there was reason to consider that reduced synaptic activity might actually be harmful to synapses, since in 2009 we published also in the Journal of Neuroscience that synaptic activation protected cultured neurons of Tg2576 mice against synaptic damage, even though Aβ secretion was increased, most likely because synaptic activity caused intracellular Aβ to decrease. Thus, active synapses were happy with extracellular Aβ up and intracellular Aβ down! Therefore, it was not surprising when we found that, even though plaques were decreased, decreasing synaptic activity by removal of whiskers actually increased intraneuronal Aβ and damaged synapses, as seen both by loss of synaptophysin and electron microscopy (Tampellini et al., 2010).

We confirmed this finding using a second model of decreased synaptic activation—putting the mice to sleep. As reported by Holtzman and colleagues (Kang et al., 2009), we also found that sleep reduced plaque burden (Tampellini et al., 2010). However, again we looked at intraneuronal Aβ and synapses, and despite reduced plaques, intraneuronal Aβ was increased and synaptophysin was reduced in the mice made to sleep.

Finally, while loss of synaptophysin and frank loss of synapses, as seen by electron microscopy, seemed not to be a good thing, we wanted to be even more certain and did behavioral testing. Consistent with the deterioration in the synapses, the Alzheimer’s transgenic mice that had been sedated did worse on memory testing despite having reduced plaques!

So what is the role of synaptic activity effects on Aβ and synapses in AD? It does not seem to be as simple as Bero and colleagues suggest. Yes, areas of high synaptic activity appear prone to plaque formation, but decreasing (normal) synaptic activity increases intraneuronal Aβ, worsens synaptic degeneration, and impairs memory. These are important data that should not be ignored, particularly if one is considering modulation of synaptic activity as a potential therapeutic or prophylactic intervention. On the other hand, our work is not the whole story either—synaptic hyperexcitability and seizures also occur in AD and may be detrimental (another story), and blocking such hyperactivity may be beneficial.

The work begun by Malinow and Holtzman relating synaptic activity and Aβ is crucial, and clearly the relationships are complex. We believe that some of the complexity is explained by considering that intraneuronal Aβ also plays a pathogenic role in disease and is modulated by activity. However, whether or not one thinks about intraneuronal Aβ, the negative effects of decreasing synaptic activity on synaptophysin levels, synaptic density counts, and cognitive performance are real.

References:
Tampellini D, Capetillo-Zarate E, Dumont M, Huang Z, Yu F, Lin MT, Gouras GK. Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci. 2010;30(43):14299-304. Abstract

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;29(31):9704-13. Abstract

View all comments by Gunnar K. Gouras
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View all comments by Davide Tampellini

We would like to reply to comments by Gouras and colleagues regarding our manuscript. Gouras, Lin, and Tampellini state, “Both the paper by Bero and colleagues and the Alzforum news story make a tacit assumption concerning the relationship between synaptic activity and β amyloid-related synapse dysfunction: that reducing plaque by reducing activity-driven secretion of Aβ is good for the brain. But is this assumption true?” We must point out that we did not make the tacit assumption being stated in any way.

We would like to clarify the principal focus of our study: As deposition of amyloid plaques in specific brain regions is a fundamental feature of AD, we sought to elucidate the mechanisms that regulate brain region-specific amyloid deposition in AD. Using APP transgenic mice (Tg2576), we found that the steady-state level of neuronal activity in each brain region predicted interstitial fluid (ISF) Aβ levels and plaque deposition in a region-specific manner. We next found that physiological neuronal activity was sufficient to dynamically regulate ISF Aβ levels by acutely...  Read more

We would like to reply to comments by Gouras and colleagues regarding our manuscript. Gouras, Lin, and Tampellini state, “Both the paper by Bero and colleagues and the Alzforum news story make a tacit assumption concerning the relationship between synaptic activity and β amyloid-related synapse dysfunction: that reducing plaque by reducing activity-driven secretion of Aβ is good for the brain. But is this assumption true?” We must point out that we did not make the tacit assumption being stated in any way.

We would like to clarify the principal focus of our study: As deposition of amyloid plaques in specific brain regions is a fundamental feature of AD, we sought to elucidate the mechanisms that regulate brain region-specific amyloid deposition in AD. Using APP transgenic mice (Tg2576), we found that the steady-state level of neuronal activity in each brain region predicted interstitial fluid (ISF) Aβ levels and plaque deposition in a region-specific manner. We next found that physiological neuronal activity was sufficient to dynamically regulate ISF Aβ levels by acutely trimming or stimulating the whiskers on one side of the mouse facial pad while performing in vivo microdialysis in contralateral barrel cortex. Finally, we utilized longitudinal in vivo multiphoton microscopy to demonstrate that longer-term (28-day) unilateral whisker trimming was sufficient to prevent amyloid plaque formation and growth in contralateral barrel cortex, suggesting that physiological neuronal activity regulates amyloid plaque growth dynamics in living brain. Together, these data suggest that physiological neuronal activity regulates ISF Aβ levels and plaque deposition, and that regional differences in steady-state neuronal activity likely represent a key determinant of region-specific amyloid deposition in AD.

The experiments described in the present paper did not aim to address whether intra- or extracellular Aβ assemblies represent the primary toxic Aβ species in AD. The pathological consequences of Aβ aggregation and extracellular Aβ deposition are well documented. However, intraneuronal Aβ accumulation may represent an additional mechanism of Aβ toxicity. This was not addressed in our study.

Finally, if chronically elevated neuronal activity in specific brain regions was protective against AD neuropathology and its consequences, one might expect brain regions that exhibit greater neuronal activity throughout life to be less vulnerable to AD neuropathology. However, brain areas that are hypothesized to exhibit elevated neuronal activity throughout life (collectively termed the “default-mode network”) are precisely those that are most vulnerable to AD neuropathology. Further, these areas show dysfunction in cognitively normal people with amyloid deposition (Sperling et al., 2009; Hedden et al., 2009).

Therefore, though neuronal activity forms the basis of brain function, chronic elevation of activity-dependent production and secretion of Aβ in specific brain regions appear to represent key determinants of region-specific amyloid deposition in AD. Of course, one would not want to globally suppress neuronal activity as any kind of therapy, or prevention of AD, with drugs such as sedatives or similar agents. However, we believe that further study of neuronal network modulation by environmental or even pharmacological means is warranted, not only to better understand network vulnerability to disease, but also potential therapeutic avenues.

References:
Sperling RA, Laviolette PS, O'Keefe K, O'Brien J, Rentz DM, Pihlajamaki M, Marshall G, Hyman BT, Selkoe DJ, Hedden T, Buckner RL, Becker JA, Johnson KA. Amyloid deposition is associated with impaired default network function in older persons without dementia.Neuron. 2009 Jul 30;63(2):178-88. Abstract

Hedden T, Van Dijk KR, Becker JA, Mehta A, Sperling RA, Johnson KA, Buckner RL. Disruption of functional connectivity in clinically normal older adults harboring amyloid burden. J Neurosci. 2009 Oct 7;29(40):12686-94. Abstract

View all comments by Adam Bero
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