A Critical Function for β-Amyloid Precursor Protein in Neuronal Migration Revealed byIn UteroRNA Interference

Abstract

Physiological processing of the ␤-amyloid precursor protein (APP) generates amyloid ␤-protein, which can assemble into oligomers that mediate synaptic failure in Alzheimer's disease. Two decades of research have led to human trials of compounds that chronically target this processing, and yet the normal function of APP in vivo remains unclear. We used the method of in utero electroporation of shRNA constructs into the developing cortex to acutely knock down APP in rodents. This approach revealed that neuronal precursor cells in embryonic cortex require APP to migrate correctly into the nascent cortical plate. cDNAs encoding human APP or its homologues, amyloid precursor-like protein 1 (APLP1) or APLP2, fully rescued the shRNA-mediated migration defect. Analysis of an array of mutations and deletions in APP revealed that both the extracellular and cytoplasmic domains of APP are required for efficient rescue. Whereas knock-down of APP inhibited cortical plate entry, overexpression of APP caused accelerated migration of cells past the cortical plate boundary, confirming that normal APP levels are required for correct neuronal migration. In addition, we found that Disabled-1 (Dab1), an adaptor protein with a well established role in cortical cell migration, acts downstream of APP for this function in cortical plate entry. We conclude that full-length APP functions as an important factor for proper migration of neuronal precursors into the cortical plate during the development of the mammalian brain.

Histone Deacetylase Inhibitor Valproic Acid Inhibits Cancer Cell Proliferation via Down-regulation of the Alzheimer Amyloid Precursor Protein

“…Interestingly, a recent study using short hairpin RNA silencing in utero could clearly demonstrate that the regulation and amount of full-length APP is essential for the proper migration of neurons in the developing cerebral cortex suggesting that dysregulation might have an impact on cortical development (56). In good agreement with previous studies, we could demonstrate that overexpression of APP induces increased cellular proliferation compared with mock-transfected controls.…”

Role of Cystatin C in Amyloid Precursor Protein-induced Proliferation of Neural Stem/Progenitor Cells

“…Our studies have shown that APP expression is increased in the olfactory neuroepithelium at the developmental stage when neurogenesis and neurite outgrowth begin (15). Similarly, APP has been reported to regulate a number of developmental functions including neuronal migration (16) and cell growth (17,18). A role for APP in cell growth is supported by the rapid up-regulation of APP that occurs in response to axonal injury (19 -21).…”

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

“…Indeed, the peak period of sensitivity to APP 96-110 is also the period in which agents that interfere with the trophic actions of neurotransmitters exhibit their greatest potency in causing malformations [5,9,11,12,16,19,27,36], suggesting a convergence of these disparate agents on a common set of end pathways regulating embryogenesis. APP 96-110 has neurotrophic activity that is important for its participation in brain development and plasticity [35,37,45,48,53] particularly so for ACh systems [25]. In keeping with this interpretation, membrane-permeable ACh agonists were the most effective agents offsetting the adverse effects.…”

“…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].…”