A heparin-binding domain in the amyloid protein precursor of Alzheimer's disease is involved in the regulation of neurite outgrowth

Abstract

The amyloid protein precursor (APP) of Alzheimer's disease is synthesized as an integral transmembrane protein that is released from cells in culture following proteolytic cleavage. The function of released APP is not known, although there is evidence that the protein may bind to components of the extracellular matrix (ECM). In the present study, substratum-bound APP stimulated neurite outgrowth in cultures of chick sympathetic and mouse hippocampal neurons. This effect was dependent upon the presence of substratum-bound heparan sulfate proteoglycans (HSPG). The effect of APP on neurite outgrowth was comparable to that of laminin. A 14 K N-terminal fragment of APP was found to bind heparin and a region close to the N-terminus of APP (residues 96-110) identified as a potential heparin-binding domain based on secondary structure predictions and molecular modeling. Mutagenesis of three basic residues (lysine-99, arginine-100, and arginine-102) resulted in a recombinant protein (APPhep) with decreased heparin-binding capacity. A peptide homologous to the heparin-binding domain was synthesized and found to bind strongly to heparin and to inhibit binding of 125I-labeled APP to heparin (IC50 approximately 10(-7) M). The peptide blocked the effect of APP on neurite outgrowth (IC50 approximately 10(-7) M), whereas two other peptides homologous to other domains in APP had no effect. The results indicate that the binding of APP to HSPG in the ECM may stimulate the effects of APP on neurite outgrowth.

Truncated β-amyloid peptide channels provide an alternative mechanism for Alzheimer’s Disease and Down syndrome

“…However, in a double transgenic mouse study with overexpressed ADAM10 and human APP that increased α-secretase activity, AD initiation and progression were limited (37). However, this protection could be caused by several factors, including (i) increased amounts of APP sα , a neurotrophic and neuroprotective factor (38,39) that could overwhelm the toxic effects of p3; (ii) diversion of more toxic Aβ 1-40/42 to nonamyloidogenic pathway (37,40); and (iii) potential additional neuroprotective effects mediated by many non-APP substrates (e.g., Notch, EGF, and β-cellulin) of ADAM10 (41). Significantly, transgenicmouse models do not fully represent human AD pathology (42), thus complicating direct clinical conclusions.…”

Interaction between the zinc(II) and the heparin binding site of the Alzheimer's disease βA4 amyloid precursor protein (APP)

“…APP binding to heparin in vitro suggests that APP growth stimulation may be mediated through this heparin-binding site in vivo. In addition, a low affinity APP heparin binding site located within residues 96-110 was shown to be involved in the regulation of neurite outgrowth [30]. This site binds three orders of magnitude less tightly to heparin than the high affinity site described here.…”

Amyloid precursor protein 96–110 and β-amyloid 1–42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids

“…Nevertheless, recent work points to important roles of amyloid precursor protein (APP) in neurodevelopment, neural cell migration, synaptogenesis and synaptic plasticity, connoting an important neurotrophic role [35,37,48,53]. Indeed, although APP is an integral membrane protein, a specific 15 amino acid sequence in positions 96-100 (NWCKRGRKQCKTHPH), located within the extracellular domain of the parent protein, represents a proteoglycan-binding domain that specifically controls neurite outgrowth and other aspects of neurodevelopment [45]. Accordingly, introduction of the free peptide itself interferes with the natural neurotrophic functions of APP, resulting in impaired neuritogenesis [45].…”

“…Indeed, although APP is an integral membrane protein, a specific 15 amino acid sequence in positions 96-100 (NWCKRGRKQCKTHPH), located within the extracellular domain of the parent protein, represents a proteoglycan-binding domain that specifically controls neurite outgrowth and other aspects of neurodevelopment [45]. Accordingly, introduction of the free peptide itself interferes with the natural neurotrophic functions of APP, resulting in impaired neuritogenesis [45]. APP thus joins other neuropeptides that have unique functions in the developing brain, such as acetylcholinesterase, which similarly plays a structural role in neurite growth [23,47], and opioid growth factor, which negatively modulates neural cell replication and growth [54,55].…”