Beker S, Kellner V, Kerti L, Stern EA.
Interaction between amyloid-β pathology and cortical functional columnar organization.
J Neurosci. 2012 Aug 15;32(33):11241-9.
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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.
Pearson RC, Esiri MM, Hiorns RW, Wilcock GK, Powell TP.
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.
Beach TG, McGeer EG.
Senile plaques, amyloid beta-protein, and acetylcholinesterase fibres: laminar distributions in Alzheimer's disease striate cortex.
Acta Neuropathol. 1992;83(3):292-9.
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.
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 Oct 27;30(43):14299-304.
Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM.
Neuronal activity regulates the regional vulnerability to amyloid-β deposition.
Nat Neurosci. 2011 Jun;14(6):750-6.
Capetillo-Zarate E, Gracia L, Yu F, Banfelder JR, Lin MT, Tampellini D, Gouras GK.
High-resolution 3D reconstruction reveals intra-synaptic amyloid fibrils.
Am J Pathol. 2011 Nov;179(5):2551-8.
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