A Deeper Look into the Pathology..

Of the genes for the early onset forms of AD, the genes amyloid precursor protein (APP), presenilin I, and presenilin II are integral membrane proteins that probably interact with the apolipoprotein E protein (apoE) within the endosomal-lysomal pathways of neurons. The apoE protein was found to have variable binding to the amyloid ß-protein fragment (Aß) of the APP gene and the tau in an isoform-specific manner. This ApoE4 was shown to bind synthetic ß-amyloid more tightly than apoE3, as this reaction resulted in a rapid formation of NFTs. We know that APP is one of the peptides that is characteristic of the plaque pathology of AD and that apoE was found to be deposited in the amyloids formed in distinct proteins.

It is interesting to note that the ApoE3 interacts with both tau and MAP2c at the microtubule binding repeat domain when apoE4 is less tightly bound. This supports a hypothesis that apoE3 and apoE2 protect that microtubule binding domain of tau from binding to itself, that would form paired helical filaments and NFTs, and protecting the site.

ApoE is immunoreactive with these plaques, vascular amyloid and (NFTs). The tau protein is the major fibrillary component of these tangles. It was noted that there was also apoE immunoreactivity in neurons without NFTs. mRNA for ApoE was found in increased amounts in astrocytes in AD but there was no evidence that the neurons expresses the mRNA for apoE. It was then suspected that the apoE could be involved in intraneuronal metabolism. Mechanisms for transport into the cell of apoE was speculated, as well as why it wasn't affected by lysosomal degradation, to explain why apoE interacted with tau in the cytoplasm of the neuron.

There are a few known receptors that allow transport of the this protein into the cell. The most abundant on neurons is the low density lipoprotein-related receptor (LRP). This receptor has a mechanism that allows the transport of peptides into the cytoplasm without having to go through endosomal transport. Another receptor is the very low density lipoprotein receptor (VLDL), as this newly discovered receptor is also localized in plaques in the human brain. Though there is still debate as to the major mode of transport into the cell, the fact remains that apoE protein is located in the neuronal cytoplasm. It is suggested that apoE is not needed for tau to perform its function, but rather that apoE3 and apoE2 may enhance this function over time by protect tau from forming PHF, as NFTs consist primarily of highly phosphorylated PHF. It can be said that the density of Aß deposition in the plaques is a function of the APOE genotype and duration of the disease. Survival is related to the age of onset and not to the APOE genotype. Though the binding activity of apoE is evident, there is no compelling evidence to suggest that these interactions cause the disease rather than being a result and consequence.

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