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Paradigm shift metals toxicity and AD

  1. interestingtome

    1,847 Posts.
    Paradigm shift redefining molecular, metabolic and structural events in Alzheimer’s disease involves a proposed contribution by transition metals. Defined lengthy preclinical stage provides new hope to circumvent advancement of disease- and age-related neurodegeneration
    Franco Cavaleri
    In press, medical hypotheses

    It is estimated that 5.5 Million North Americans suffer from varying degrees of Alzheimer’s disease (AD) and by the year 2050 it may be one in 85 people globally (100 Million). It will be shown that heavy metal toxicity plays a significant role in sporadic AD. Although current literature speaks to involvement of metal ions (via Fenton Reaction), studies and reviewers have yet to link cellular events including known structural changes such as amyloid plaque development to this metal toxicity the way it is proposed here.

    Contrary to the current AD model which positions BACE1 (β-secretase) as an aberrant or AD-advancing enzyme, it is proposed herein that the neuron’s protective counteraction to this metal toxicity is, in fact, a justified increase in BACE1 activity and amyloid precursor protein (APP) processing to yield more secreted APP (sAPP) and β-amyloid peptide in response to metal toxicity. This new perspective which justifies a functional role for APP, BACE1 enzyme activity and the peptide products from this activity may at first appear to be counterintuitive.

    Compelling evidence, however, is presented and a mechanism is shown herein that validate BACE1 recruitment and the resulting β-amyloid protein as strategic countermeasures serving the cell effectively against neuro-impeding disease. It is proposed that β-amyloid peptide chelates free heavy metals and the sequestered metal is chaperoned as a metallo-peptide to cross the plasma membrane and aggregate as amyloid plaques extracellularly.The BACE1 countermeasure is not genetic or metabolic aberration; and this novel conclusion demonstrates that it must not be inhibited as currently targeted. APP, BACE1, β-amyloid peptide, and sAPP play positive roles against the preclinical oxidative load that predates AD symptoms for as long as 20 years.

    A healthy neuron may tolerate free metal toxicity, such as iron in the case of injury-induced amyloid, for as long as twenty years due to this very BACE1 activity. In later stages, the uncontrolled metals and ROS are compounded by other factors which together overcome this BACE1/ β-amyloid protein countermeasure. This results in a sudden increase in IL-1 leading to Tau’s hyperphosphorylation as cited and eventually to Tau dissociation from the microtubule cytoskeleton interrupting cell trafficking. At this later stage of AD the β-amyloid protein which once served as a vehicle to escort toxic metals to the extracellular medium is no longer translocated due to interruption of trafficking and now accumulates facilitating hyper-oxidative ROS levels and contributes to irreversible neuron apoptosis.

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