. Proteomic analysis of in vivo phosphorylated synaptic proteins. J Biol Chem. 2005 Feb 18;280(7):5972-82. PubMed.

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  1. With reference to Alzheimer disease and memory mechanisms, this paper identifies 600 phosphorylation sites on synapses. Synapse formation and destruction are critical aspects of memory. Further, phosphorylation is a critical part of synaptic plasticity, as discussed in this paper, which has delineated many of the critical phosphorylation sites.

    What is missing, especially with regard to Alzheimer disease, is how the Alzheimer process, which may require aberrant β amyloid, is responsible for causing the microtubule-associated protein tau to become abnormally phosphorylated. Accordingly, only CDK5 is mentioned, but not GSK3β (glycogen-synthase-kinase-3β), which is thought to be relevant for AD. Other relevant kinases that phosphorylate tau may include MAPK, CDK2, PKA, CAMKII, MARK (of these only PKA was mentioned), though these other kinases may not phosphorylate tau at the Alzheimer-relevant sites.

    Of course, Alzheimer-critical tau phosphorylation may occur in the processes (dendrites and axons) rather than in the synapses, and, therefore, may be more associated with transport of proteins rather than their arrangements in the synapses. Consequently, this study may address phosphorylation issues in an area different from the relevant micro-anatomical locus for AD. But phosphorylation is relevant to neuroplasticity and relevant to the tau hyper-phosphorylation associated with Alzheimer disease. Consequently, this paper provides further elucidation of the important relationship between neuroplasticity and Alzheimer disease.

    The question that still needs greater attention is: What is the fundamental causative factor in Alzheimer disease? Most focus has been given to the rare familial genes associated with amyloid. Less attention has been paid to the ApoE gene and the specific relationships that its various proteins have in Alzheimer etiology. Since these ApoE proteins appear to play a role in cholesterol metabolism, and this metabolism must play a role in synaptic plasticity, then there is a clear need to establish the link between the roles of the various ApoE proteins
    (4,3,2) and the control of the phosphorylation activities associated with synapse formation and destruction.