16 November 2002. In a transgenic mouse model of Alzheimer's amyloidosis, lesioning the perforant pathway from the entorhinal cortex (EC) to the hippocampus substantially reduces the amyloid burden of the hippocampus. This is the conclusion of two similar studies published in yesterday's Journal of Neuroscience.
It has been known for almost a decade that amyloid precursor protein (AβPP) is transported along axons from the cell body toward the synaptic terminals. In particular, it has been shown that most of the AβPP in the dentate gyrus of the hippocampus in axons is produced by EC cells and is transported along the perforant pathway (Buxbaum et al., 1998;). While it would be tempting to jump to the conclusion that this pool of AβPP is the source of Aβ in the dentate gyrus—and that this Aβ, in turn, is secreted by axon terminals to help form extracellular amyloid plaques—this has not been proven. Evidence that AβPP from the EC contributes to the amyloid burden in the hippocampus now comes from two studies in which the perforant pathway was lesioned in mice harboring both the human AβPP Swedish and presenilin1-δE9.
Vassilis Koliatsos and colleagues at Johns Hopkins University in Baltimore, Maryland, aspirated out the EC, whereas Sam Sisodia and colleagues at the University of Chicago, Illinois, and Johns Hopkins interrupted the pathway with knife lesion, but otherwise, the structure of the experiments was very similar. Both groups found that perforant pathway lesion reduced the amyloid burden in the hippocampus to half that of the unlesioned control side of the brain. When they focused in on the dentate gyrus, both groups found that the reduction was even greater on the lesioned side.
In addition, both groups noticed that the lesion significantly reduced the number of dystrophic neurites (which have been found surrounding amyloid deposits in both humans and transgenic mouse models). Similarly, Sisodia's group found there was less astrogliosis in the hippocampus that had lost its EC innervation.
These findings support the idea that the EC is a major source of the amyloidogenic Aβ in the dentate gyrus. Sisodia and colleagues note that the results support the notion of amyloid deposits as dynamic structures that are constantly built up by one set of processes and simultaneously attacked by another process. By cutting off the EC source of Aβ, they suggest, the equilibrium shifts from the deposition side to the clearance side of the equation.
It is still not certain, however, that the AβPP transported from the EC is primarily converted to Aβ that finds its way into extracellular plaques, because new evidence indicates that Aβ accumulates inside nerve terminals (see Takahashi et al., 2002;; see also comment below and the upcoming Alzforum live chat on intraneuronal Aβ). Sisodia and colleagues performed one experiment to ask whether axon terminals (as opposed to the local dentate gyrus cells) are the major source of Aβ extracellular plaques. By lesioning the perforant pathway in animals too young to have plaques, they gave the brain a chance to rewire these areas. They found that these animals had equal levels of amyloid burden on lesioned and unlesioned sides of the brain, suggesting the replacement axons were the source of this Aβ.—Hakon Heimer.
Lazarov O, Lee M, Peterson DA, Sisodia SS. Evidence that synaptically released b-amyloid accumulates as extracellular deposits in the hippocampus of transgenic mice. J Neurosci. 16 Nov 2002;22(22):9785-93. Abstract
Sheng JG, Price DL, Koliatsos VE. Disruption of corticocortical connections ameliorates amyloid burden in terminal fields in a transgenic model of Ab amyloidosis. Abstract