. Dynamic analysis of amyloid β-protein in behaving mice reveals opposing changes in ISF versus parenchymal Aβ during age-related plaque formation. J Neurosci. 2011 Nov 2;31(44):15861-9. PubMed.

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  1. These are two very interesting papers discussing the production of Aβ with age. Soyon Hong and Dennis Selkoe's work in awake, behaving mice is particularly interesting as it elegantly shows that dense plaques are in equilibrium with soluble Aβ in the parenchyma, both sequestering exogenously added Aβ and acting as a source of Aβ when γ-secretase is inhibited. This supports the body of evidence showing that plaques are toxic to the nearby neurites and synapses because they are a local source of soluble Aβ species.

    View all comments by Tara Spires-Jones
  2. The paper by Hong and colleagues is a valuable contribution to our understanding of interstitial β amyloid in the brain with AD pathogenesis. We had considered examining interstitial fluid (ISF) Aβ, but turned to our cultured neuron system because we felt that even if there was reduced ISF Aβ prior to plaques, microdialysis would be unable to fully tease apart changes in secretion from sequestration to extracellular aggregates.

    Our cultured neuron model has served us well in the past. With it we showed for the first time Aβ-dependent reductions in surface glutamate receptor subunits (Almeida et al., 2005) and Aβ-dependent alterations in the multivesicular body sorting, but not recycling endocytic pathways (Almeida et al., 2006). Moreover, our AD transgenic compared to wild-type neuron system was really put to the test when we saw that synaptic activity protected synapses of AD transgenic neurons while inducing Aβ secretion but reducing intraneuronal Aβ (Tampellini et al., 2009). This was borne out in vivo when we examined synapses and behavior in APP mice using two different models to inhibit cerebral activity (including the barrel cortex): Transiently inhibiting activity reduced plaques, but increased intraneuronal Aβ and synaptic damage, and worsened behavior in AD transgenic mice. Thus, synapse damage and behavioral dysfunction correlated with intraneuronal Aβ but not plaques (Tampellini et al., 2010).

    For our current paper, we returned to cultured neurons to more carefully define the intra- versus extracellular pools of Aβ40 and Aβ42 over time in culture, during which AD transgenic neurons develop progressive AD-like synapse alterations. In fact, our data of increasing intraneuronal but declining extracellular Aβ in AD transgenic neurons fit well with those on ISF Aβ by Hong et al. In contrast, our conclusions differ. We consider both the intra- and extracellular Aβ pools, while Hong and colleagues—like so many in the field—only consider the extracellular pools. A membrane-associated pool is also mentioned in their discussion, as an explanation for why they could not detect Aβ dimers in ISF. Our explanation would be that Aβ oligomers are clogging up within neurons in AD, and become extracellular following destruction of neurites. The latter is not just a hypothesis; there are plenty of electron microscopy data in AD transgenic mice and also human AD brains to back this up (Takahashi et al., 2002; Takahashi et al., 2004). But for those who are not familiar with immuno-EM and might find it difficult to interpret, please take a look at our most recent pathological study in the current issue American Journal of Pathology (Capetillo-Zarate et al., 2011). This paper clearly shows intraneuronal and even isolated intra-synaptic Aβ42 accumulation, oligomerization, and fibrillization using easily viewable 3D movies.

    Hong and colleagues provide valuable data that we could not using our system. They show that plaques appear to be a source of releasable Aβ, since the decrease of ISF Aβ42 in the setting of γ-secretase inhibition was less pronounced in the presence compared to absence of plaques. Their new data on native forms of Aβ in brain are also of considerable interest. Together, our publications are complementary and not mutually exclusive, and move us a bit further in our understanding of this complex illness.

    References:

    . Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses. Neurobiol Dis. 2005 Nov;20(2):187-98. PubMed.

    . Beta-amyloid accumulation impairs multivesicular body sorting by inhibiting the ubiquitin-proteasome system. J Neurosci. 2006 Apr 19;26(16):4277-88. PubMed.

    . 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.

    . Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci. 2010 Oct 27;30(43):14299-304. PubMed.

    . Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol. 2002 Nov;161(5):1869-79. PubMed.

    . Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci. 2004 Apr 7;24(14):3592-9. PubMed.

    . High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils. Am J Pathol. 2011 Nov;179(5):2551-8. PubMed.

  3. This paper by Selkoe’s group is an important contribution to our understanding of amyloid-β (Aβ), an Alzheimer’s disease (AD) neurotoxin metabolism in plaque-free and plaque-rich brain. The authors used a well-established microdialysis technique to study the dynamics of soluble Aβ clearance by sampling and analyzing soluble Aβ species in the interstitial fluid (ISF) of young and old transgenic mice carrying an hAPP mini-gene with familial AD mutations. The study not only provides strong evidence for the hypothesis that cerebral amyloid deposits act as a sink for soluble Aβ in the ISF, but also suggests that amyloid plaques act as a large reservoir and a major source of soluble Aβ42 in the ISF.

    Mounting evidence suggests that diminished Aβ clearance from the brain, but not alteration in Aβ production (also confirmed in the present study), leads to Aβ accumulation in the brains of AD patients. Targeting Aβ clearance pathways (reviewed recently by Zlokovic, 2011) may help in correcting the faulty clearance from AD brain and across the blood-brain barrier.

    References:

    . Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011 Dec;12(12):723-38. PubMed.

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  1. Monomeric Aβ’s Disappearing Act in AD Brain: Two Theories