Amyloid-β-stimulated plasminogen activation by tissue-type plasminogen activator results in processing of neuroendocrine factors

Alzheimer's disease brain is characterized by the abundant presence of amyloid deposits. Accumulation of the major constituent of these deposits, amyloid-β (Aβ), has been associated with decreased neurotransmission, increased neuronal cell death, and with cognitive decline. The mechanisms underlying these phenomena have not yet been fully elucidated. We have previously shown that amyloid peptides like Aβ bind tissue-type plasminogen activator (tPA) and cause enhanced plasmin production. Here we describe the identification of five major neuronal cell-produced Aβ-associated proteins and how Aβ-stimulated plasmin formation affects their processing. These five proteins are all neuroendocrine factors (NEFs): chromogranins A, B and C; truncated chromogranin B; and VGF. Plasminogen caused processing of Aβ-bound (but not soluble) tPA, chromogranin B and VGF and the degradation products were released from Aβ. Processing of the neuroendocrine factors was dependent on tPA as it was largely abrogated in tPA−/− cells or in the presence of a specific tPA-inhibitor. If plasmin indeed produces NEF-derived peptides in vivo, some of these peptides may have biological activity, for instance in regulating neurotransmitter release that may affect the pathology of Alzheimer's disease.