. Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network. Neuron. 2010 Nov 4;68(3):428-41. PubMed.

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  1. I’ve read the article and find it to be interesting and to provide important new information. It demonstrates that overproduction of β amyloid in the entorhinal cortex can lead to synaptic aberrations in the hippocampus. This supports the view that pre-synaptic Aβ can lead to synaptic abnormalities. It would have been interesting to measure synaptic properties in EC neurons, particularly in regions where they receive afferent input from non-overexpressing regions, to see if they are equally or more affected, than hippocampal neurons. This could address if pre-synaptic or post-synaptic Aβ has more deleterious effects. From the deposition data they show, the EC appears to be more affected, suggesting that cell body and dendritic Aβ may be more abundant.

    The mechanism by which this ”trans-synaptic” effect is transmitted will be interesting to identify.

  2. The paper by Julie Harris and colleagues is an important contribution toward understanding the role of synaptic networks in progression of neuronal dysfunction and Aβ deposition. They produced and studied transgenic mouse models with region-specific overexpression of mutant APP in the entorhinal cortex (EC) layer II/III neurons, and have shown that Aβ deposition occurs in the terminal projection zones of these neurons, and that functional impairments can cross synapses. In this model, such abnormalities occur initially in the EC neurons and extend to the hippocampal cells. As the authors mentioned, the EC is one of the earliest affected regions in AD. It has to be noted, however, that in humans, the early pathology takes the form of neurofibrillary tangles, which are composed of abnormally phosphorylated tau protein (Braak and Braak, 1991). It is well known that tau abnormalities precede Aβ deposition in this area in AD.

    There is increasing evidence that intracellular accumulation of abnormal proteins such as tau and α-synuclein may be transferred from cell to cell, propagating by a prion-like mechanism (Goedert et al., 2010; Nonaka et al., 2010). It will be interesting to see whether abnormal intracellular proteins propagate through the synapses in similar transgenic mouse models that selectively overexpress mutant tau or α-synuclein in areas where they first accumulate in diseases.

    References:

    . Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239-59. PubMed.

    . The propagation of prion-like protein inclusions in neurodegenerative diseases. Trends Neurosci. 2010 Jul;33(7):317-25. PubMed.

    . Seeded aggregation and toxicity of {alpha}-synuclein and tau: cellular models of neurodegenerative diseases. J Biol Chem. 2010 Nov 5;285(45):34885-98. PubMed.

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