. Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci. 2011 Jun;14(6):750-6. PubMed.

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  1. 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.

    View all comments by Gunnar Gouras
  2. This is a very nice study. It provides further support that synaptic activity controls neuronal release of Aβ, and argues that synaptic activity may be the dominant factor controlling Aβ levels and plaque formation (rather than the recently proposed changes in Aβ removal). It will be very interesting in the future to correlate synaptic activity levels with Aβ release and plaque formation at a shorter distance scale (tens of microns).

  3. The data here are beautiful and compelling, especially the demonstration of the temporal relationship between the accumulation of oligomers and the changes in interstitial fluid (ISF) lactate. Once again, the chicken-and-egg test shows that oligomerization is upstream of neurotoxicity, and not vice versa (although that relationship may become less black and white as the disease progresses).

    I think that there are some details that may have been glossed over for the sake of the narrative:

    1. “Neuronal activity” is described as though this were some homogenous, unitary phenomenon, when, in fact, the moment to moment, spatial summation of dozens of chemical signals arriving per second at the soma or at the synapse leads to highly diverse signaling and, in turn, a wide spectrum of Aβ40 and Aβ42 generation. I completely agree that this is not the whole story, but I would rank this as the determinant of some range of Aβ levels that will vary from one microenvironment to another.

    2. Different signals are differentially amyloidogenic. The soma versus the nerve terminal may be differentially competent for generating Aβ. Some signals regulate the relative utilization of α- versus β-secretase pathways, while other signals differentially regulate generation of Abeta42 versus 40. A slightly different but relevant point is that there are amyloidogenic pathways that may be more constitutive and others that may be more highly regulated (e.g., autophagy, nerve terminal generation of Aβ).

    3. The fraction of catabolized APP holoprotein or CTFs that gives rise to discrete fragments is tiny and cannot be predicted by steady levels of either holoAPP or APP CTFs. This is true in cell lines as well as tissue, and I would never try to predict Aβ levels from levels of APP or any APP fragment.

    4. Rarely mentioned in an “Aβ clinicopathological spatiotemporal specification” discussion, such as arises here, is an amazing fact that dates back to 1995 when the first authentic APP transgenic mouse was analyzed histologically: Regardless of whether the prion promoter or the Thy1 promoter was used to drive totally unnatural patterns of overexpression of human APP transgenes, the regional and laminar accumulation of plaque pathology recapitulated, virtually perfectly, the pattern observed in the human AD brain. This is pretty amazing when you think about it. How did the mouse’s brain “know” what to do with human APP regionally and according to cortical levels following overexpression on pan-neuronal or pan-cellular promoters? There are clearly pre-existing specifiers of the deposition pattern. The regional levels of secretases, insulin degrading enzyme, and neprilysin, and the respective states of activation, all play their respective roles, but what has been less clearly articulated is something that seems obvious to me—there is almost certainly one or more extracellular matrix pro-aggregation or pro-oligomerization factors that play important roles in specifying the pattern of regional and laminar conversion of soluble Aβ to oligomeric and fibrillar Aβ. These local factors (metals, glycosaminoglycans, etc.) may well represent good amyloid-lowering targets, and have been picked up with variable success (by Ashley Bush and Prana Biotechnology with CHQ and PBT2 on the upside and by Neurochem with Alzhemed on the downside).

  4. 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.

    View all comments by Adam Bero
  5. The Alzforum recently hosted a vivid Webinar that—among others—challenged the absolute supremacy of amyloid-β (Aβ) as the leading cause of Alzheimer’s disease (AD) neuropathology. Indeed, it is now accepted by an increasing number of investigators that AD-specific neuronal dysfunction and death could occasionally occur without being accompanied by the typical accumulation and aggregation of Aβ in specific brain regions. Yet, this hallmark of AD is still the one that unequivocally signals the presence of the disease for clinicians and investigators alike. Therefore, those who attempt to explain the AD process necessarily have to explain the accumulation and aggregation of Aβ in the AD brain. They also have to explain why these processes affect some—the so-called “vulnerable”—but not other, regions of the brain.

    The present study elegantly explains—first of all—why Aβ pathology preferentially develops in the vulnerable brain regions, by showing that these vulnerable regions are those where basal neural network activity is highest. The study also shows that this is so because increased network activity leads to increased levels of extracellular, soluble Aβ—a facilitating condition for the accumulation of soluble and insoluble Aβ aggregates, including neuritic plaques. The study is a tour de force: The many and difficult experiments are well controlled, and the conclusions—while intriguing—are logical, persuasive, and thought provoking.

    In spite of these remarkable achievements, the study does not explain the intimate mechanisms that lead to increased extracellular levels of Aβ, although the authors do their best to uncover them. One by one, the authors eliminate several common-sense explanations, such as the differential clearance of Aβ in different brain regions, or local increase in the precursors of Aβ, the Aβ precursor protein (APP) and the C-terminal fragment β (CTFβ); their variability across the brain cannot explain the variability in the level of soluble Aβ. The authors speculate that the increased levels of Aβ in the regions with high network activity could result from import of Aβ produced in the soma of distant neurons located elsewhere in the brain, which project into the vulnerable regions. Indeed, recent studies cited in this paper suggest that Aβ pathology may spread through interconnected neural networks. Several years ago, we proposed that the Aβ, produced in neurons in subcortical regions such as the locus coeruleus (LC), could be provided to remote brain regions through the processes of the LC neurons, which project in the AD vulnerable regions (1-3). More recent studies proposed a similar mechanism for the delivery of pyroglutamate-Aβ, produced in LC neurons, to the AD vulnerable brain regions (4,5). These studies fully support the idea that the Aβ present in the vulnerable regions could be produced elsewhere in the brain.

    We would like to propose yet another possible mechanism by which neuronal activity could release soluble Aβ in the extracellular space, from intraneuronal pools. Recent data indicate that Aβ co-resides with catecholamine neurotransmitters, and that Aβ and catecholamines undergo co-secretion (6). Also, our recent results show that a significant fraction of the intraneuronal Aβ is produced in recycling endosomes (7), which are known to be a source for synaptic vesicle recycling. It is conceivable that this intraneuronal Aβ is incorporated in the recycled synaptic vesicles, and becomes secreted during synaptic activity. These mechanisms could thus provide an explanation for the accumulation of Aβ in regions of high neural network activity.

     References:

    See also Muresan Z, V Muresan V. Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum. 2008; Hook, V.Y., et al., Regulated secretory vesicles contain beta-amyloid peptide forms with neuropeptides and catecholamines that undergo co-secretion. Annual Meeting of the Society for Neuroscience, San Diego, November 13-17, 2010; and Muresan, V., B.T. Lamb, and Z. Muresan, DISC1 is required for the formation of intracellular Aβ oligomers, suggesting a link between schizophrenia and Alzheimer’s disease. Annual Meeting of the Society for Neuroscience, San Diego, November 13-17, 2010.

    References:

    . Neuritic deposits of amyloid-beta peptide in a subpopulation of central nervous system-derived neuronal cells. Mol Cell Biol. 2006 Jul;26(13):4982-97. PubMed.

    . Seeding neuritic plaques from the distance: a possible role for brainstem neurons in the development of Alzheimer's disease pathology. Neurodegener Dis. 2008;5(3-4):250-3. PubMed.

    . Glutaminyl cyclase contributes to the formation of focal and diffuse pyroglutamate (pGlu)-Aβ deposits in hippocampus via distinct cellular mechanisms. Acta Neuropathol. 2011 Jun;121(6):705-19. PubMed.

    . Distinct glutaminyl cyclase expression in Edinger-Westphal nucleus, locus coeruleus and nucleus basalis Meynert contributes to pGlu-Abeta pathology in Alzheimer's disease. Acta Neuropathol. 2010 Aug;120(2):195-207. PubMed.