Scientists know little about how amyloid-β deposits interact with the complex architecture of the brain. Are plaques seeded randomly, or do they develop preferentially in certain areas? In the August 15 Journal of Neuroscience, researchers led by Edward Stern at Bar-Ilan University, Ramat Gan, Israel, provide evidence for the latter. They measured Aβ distribution in the barrel cortex of AD mice, and found that plaques tended to form between the barrels, a region that is rich in inhibitory interneurons. “This is the first direct evidence that plaques disrupt columnar organization,” Stern told Alzforum. Although human brains do not contain barrels, our neocortex forms columns, suggesting these findings could apply to people, also, he added. Intriguingly, the data imply that plaques may disrupt inhibitory synaptic inputs more than excitatory, a hypothesis Stern is currently testing.

“[The paper] is a thoughtful piece of neuroanatomy that may tell us about underlying mechanisms of plaque formation. It will be interesting to see how these patterns compare to what is seen in humans,” Brad Hyman at Massachusetts General Hospital, Charlestown, wrote to Alzforum. He has collaborated with Stern in the past but was not involved in the current work.

Previous work by Hyman and colleagues showed that amyloid deposits distort neuronal connections, causing neurites to twist and synaptic responses to falter, but did not directly demonstrate effects on columns (see Knowles et al., 1999; Stern et al., 2004). Some studies of postmortem human brain have found that plaques cluster in the cortex (see Beach and McGeer, 1992), or stack in a columnar fashion (see Akiyama et al., 1993), but because cortical columns are not easily visualized in people, these studies could not directly place plaques in the neuronal architecture.

To get around this limitation, Stern and colleagues examined 20-month-old APP/PS1 transgenic mice. Mouse barrel cortex receives stimulation from the animal’s whiskers. This input arrives in layer IV of the cortex, where the barrels are easily seen as distinct physical structures. First author Shlomit Beker measured the plaque distribution in layer IV, and found significantly more deposits between barrels than within barrels. This resulted in a highly clustered pattern of plaques. Tracing the columns upward, the authors saw that this precise pattern did not hold in layer II/III, but that plaques in this layer clustered, indicating they still followed some columnar organization. By contrast, the authors found a more random distribution of plaques in the visual cortex, a region that does not organize into columns in mice.

Since most excitatory inputs to layer IV neurons are found within the barrels, and many inhibitory inputs originate from the septae between barrels, the data suggest that Aβ deposits may selectively weaken neuronal inhibition. Functionally, inhibitory interneurons in the septae mediate lateral inhibition of adjacent whiskers, sharpening the animal’s ability to discriminate edges and textures. Plaques might blunt this, in effect, widening the receptive fields of barrel neurons, Stern proposed. He is currently testing this idea using electrophysiological recordings. Intriguingly, other studies have shown that neurons near amyloid plaques become hyperactive (see ARF related news story). Some strains of AD mice are prone to epileptiform activity (see ARF related news story; ARF news story), and anti-epileptic drugs were recently reported to correct cognitive deficits in AD mice (see ARF related news story). Stern told Alzforum he is very interested in following up on the epilepsy connection, and is doing recordings from both awake and anesthetized mice to look at specific types of synaptic activity and how they relate to plaque distribution.

Thomas Beach at Banner Sun Health Research Institute, Sun City, Arizona, found the research intriguing.“ It is exciting that some of the implications and hypotheses arising from the finding can be tested in the transgenic mouse model used,” he wrote to Alzforum. “What remains tantalizing is the promise that such patterns of degeneration hold for understanding disease. (See full comment below.)

Tara Spires-Jones, who is also at Mass General and has worked with Stern in the past, agreed, suggesting that future work could look at the effects of inhibitory and excitatory circuitry on plaque deposition in the mouse. To extend the work to humans, researchers might examine postmortem brains to see if Aβ aggregates occur near inhibitory synapses, she said. She believes the paper also demonstrates that mouse barrel cortex can be a good model system for AD. Because barrel cortex is highly active, it may have some similarities to the default-mode network in human brains, which is constitutively active and one of the earliest areas to accumulate Aβ, she said. Barrel cortex is also very plastic even in adult rodents, and so could be useful for measuring whether plaque distribution predicts plasticity deficits.—Madolyn Bowman Rogers

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Comments on News and Primary Papers

  1. Beker and colleagues contribute to the important question of what circuitry and cell types are particularly vulnerable in AD transgenic models of β amyloidosis. While we and others examined the barrel cortex in AD transgenic mouse models deprived of sensory input (Tampellini et al., 2010; Bero et al., 2011), the current study made the interesting pathological observation that there is a predilection for amyloid plaques between rather than within the columns of the barrel cortex. This observation points to vulnerability of inhibitory interneurons, which might explain why cortical hyperactivity is pronounced in AD transgenic mice.

    Like many investigators, the authors focus on extracellular amyloid plaques as the pathogenic cause of alterations in inhibitory interneurons. However, the APP/PS1 mutant transgenic mice used in this study were examined at a late age, though they develop behavioral impairment prior to plaques. This means that there is dysfunction before amyloid plaques. Remarkably, we noted that GABAergic interneurons in CA1 showed early and prominent intraneuronal thioflavin S amyloid labeling (Capetillo-Zarate et al., 2011; Fig. 1C), which could be a cause of interneuronal dysfunction prior to the appearance of plaque.

    References:

    . 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.

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

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

  2. I think the results raise several questions and have some implications for the disease in humans, but I think it is also exciting that some of the implications and hypotheses arising from the finding can be tested in the transgenic mouse model used.

    For human AD, there have been quite a few published studies where investigators have been trying to make sense out of the often intricate patterns formed by amyloid plaques as well as neurofibrillary tangles. The most well known of these, by Powell and colleagues (Pearson et al., 1985), suggested that the distribution of neurofibrillary tangles predominantly to layers III and V of the cerebral neocortex was consistent with a hypothetical "spread" of the disease along cortico-cortical pathways. The authors of the current paper also cite work done by myself with Edith McGeer (Beach and McGeer, 1992), in which we suggested that the laminar pattern of amyloid plaque formation in human AD primary visual cortex might be due to excessive Aβ release as a result of loss of cholinergic, anti-amyloidogenic synaptic input.

    One of the basic issues has been whether patterns of degeneration in AD (and other neurodegenerative diseases) represent a neuroanatomical, perhaps trans-synaptic "spread" of disease, or whether the patterns are simply due to selective vulnerability. What remains tantalizing is the promise that such patterns of degeneration hold for understanding disease. As plaques are clearly distributed in a non-random manner, most often corresponding to neuronally defined cyto-architectonic compartments, it would seem that neurons are the cell types responsible, although the possibility remains that vascular cells may also produce the amyloid found in amyloid angiopathy.

    The authors' suggestion that the extracellular matrix composition might be responsible for the septal deposition within barrel cortex is also quite plausible, as in human AD it has long been considered that differences and changes in the avidity of amyloid binding to extracellular matrix molecules might underlie the varying distribution of amyloid to blood vessel walls (amyloid angiopathy) and neuropil (plaques), since such distributions are known to vary with, for example, apolipoprotein E genotypes.

    I have not read any of the cited papers showing that amyloid might preferentially depress the activity of inhibitory neurons, but it is an interesting hypothesis that should be testable in the mouse model.

    Many AD subjects develop seizures at a late stage of disease, and this could be due to decreased inhibitory activity, or also to the known loss of synaptic complexity and/or synaptic remodeling that occurs, also.

    References:

    . Anatomical correlates of the distribution of the pathological changes in the neocortex in Alzheimer disease. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4531-4. PubMed.

    . Senile plaques, amyloid beta-protein, and acetylcholinesterase fibres: laminar distributions in Alzheimer's disease striate cortex. Acta Neuropathol. 1992;83(3):292-9. PubMed.

    View all comments by Thomas Beach

References

News Citations

  1. Hyperactive Neurons and Amyloid, Side by Side
  2. Do "Silent" Seizures Cause Network Dysfunction in AD?
  3. Chicago: AD and Epilepsy—Joined at the Synapse?
  4. Anticonvulsants Reverse AD-like Symptoms in Transgenic Mice

Paper Citations

  1. . Plaque-induced neurite abnormalities: implications for disruption of neural networks in Alzheimer's disease. Proc Natl Acad Sci U S A. 1999 Apr 27;96(9):5274-9. PubMed.
  2. . Cortical synaptic integration in vivo is disrupted by amyloid-beta plaques. J Neurosci. 2004 May 12;24(19):4535-40. PubMed.
  3. . Senile plaques, amyloid beta-protein, and acetylcholinesterase fibres: laminar distributions in Alzheimer's disease striate cortex. Acta Neuropathol. 1992;83(3):292-9. PubMed.
  4. . Columnar arrangement of beta-amyloid protein deposits in the cerebral cortex of patients with Alzheimer's disease. Acta Neuropathol. 1993;85(4):400-3. PubMed.

External Citations

  1. APP/PS1 transgenic mice

Further Reading

Primary Papers

  1. . Interaction between amyloid-β pathology and cortical functional columnar organization. J Neurosci. 2012 Aug 15;32(33):11241-9. PubMed.