. 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 Harris et al. is right on target with regard to the nucleation of plaques by seeds of oligomeric Aβ that ultimately could come from cells within brain regions remote from the site of plaque formation. The favored view appears to be that the Aβ that accumulates at the terminal fields of the perforant pathway is produced locally—in pre-synaptic endosomes (1) from axonally transported full-length APP, or C-terminal fragments (CTFs) of APP (2-4). Yet a large fraction of Aβ is generated in the neuronal soma, in the endoplasmic reticulum, the trans-Golgi network, and recycling endosomes. We (5), and others (6) consistently detected Aβ-positive, vesicle-like particles along neuronal processes, suggesting that at least some of the Aβ within terminals could come from transport of the cleaved polypeptide, generated in the soma. In any case, the precursor of Aβ, or the Aβ itself, which nucleates the hippocampal deposits in the mouse models described by Harris et al., is indeed brought from the distance.

    We recently proposed a mechanism for nucleation of plaques within the cortex and hippocampus; the seeding, oligomeric Aβ is produced remotely, in the soma of brainstem neurons that project into the cortex and hippocampus (7,8). Working with cells in culture, we showed that locus coeruleus-derived neurons are particularly prone to producing intracellular Aβ oligomers that accumulate at the terminals of their processes (9). We also showed that these neuritic Aβ aggregates can become extracellular (7). While our view is that a fraction of the plaques in the cortex and hippocampus of Alzheimer’s disease (AD) brain is nucleated by Aβ oligomers released from the terminals of brainstem neurons, it is certain that Aβ seeds could originate from other brain regions as well. The study by Harris et al. points to one of them—the entorhinal cortex.

    Much remains to be done to prove that such mechanisms indeed occur in the human brain in AD. Yet it is already the time to think that—in AD—treating a brain region remote from the sites of plaque formation may not be as unrealistic as it may seem. Yes, as we spelled it out in one of our recent papers, and is clearly demonstrated by Harris et al., plaques can be seeded from the distance—a very long distance.

    See also: Muresan, Z. and V. Muresan, Brainstem Neurons Are Initiators of Neuritic Plaques. SWAN Alzheimer Knowledge Base. Alzheimer Research Forum


    View all comments by Virgil Muresan
  3. 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.


    . 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.

This paper appears in the following:


  1. Insidious Spread of Aβ: More Support for Synaptic Transmission