<p>High levels of Aβ (green helix) develop in the brain prior to the onset of Alzheimer’s pathology (top left). Longer forms of Aβ have more hydrophobic amino acid residues (gold) on remnant transmembrane domain, thereby increasing transient insertion (downward arrow) into the plasma membranes of nearby cells including endothelial cells (red). Elevated tissue levels of Aβ cause an accumulation of Aβ on the surface of the cell (several helices). Some peptide enters the endosome pathway (left). The amino termini of inserted Aβ peptides are identical to the Nicastrin-binding region of the APP intermediate C99 (not shown) and transiently bind to the γ-secretase complex (two sided arrow). Competition for Nicastrin binding and γ-secretase access reduces the processing of other substrates such as NEXT (shown). Interference with NEXT processing inhibits the production of NICD, which de-represses transcription factors such as Hes-1 and Hey-1. GSI has a similar effect. De-repression of NICD targets causes endothelial shaft cells to adopt tip cell morphology (upper right). Tip cells lead to formation of new blood vessels, and cycling of this process (looped arrow) over years and decades leads to hypervascularization (top right). This process may also occur with other extracellular cleavage (ex) products of γ-secretase (shown) creating feedback that tempers γ-secretase activity.</p
