title: Reduced expression of pain mediators and pain sensitivity in amyloid precursor protein over-expressing CRND8 transgenic mice.
abstract: β-Amyloid (Aβ) peptides are derived from the sequential cleavage of the amyloid precursor protein (APP). They are enriched in plaques present in Alzheimer's brains and thus play important roles in the pathogenesis of this disease. APP is also known to be expressed in the neurons of dorsal root ganglion (DRG) and contributes to neuronal survival and axonal growth during development. However, whether APP and Aβ peptides are involved in nociception and pathological pain states is mostly unknown. In the present study, we have used behavioral, biochemical and morphological approaches to address this issue in both adult rats and APP over-expressing CRND8 transgenic mice. We observed that the Aβ peptide (17-24) was predominantly expressed in small-sized DRG neurons of rats. Following intraplantar (i.pl.) injection of complete Freud's adjuvant (CFA), the levels of APP and Aβ peptides were significantly reduced in the ipsilateral lumbar 4-6 rat DRG. In 3-, 12- and 24-month-old CRND8 mice, pain sensitivity in response to heat and mechanical stimulation was significantly dampened compared to their age-matched wild-type littermates. In parallel with reduced pain sensitivity, the expression of pain mediators such as substance P, calcitonin gene-related peptide and transient receptor potential vanilloid-1 was significantly reduced in L4-6 DRG of CRND8 mice. Although i.pl. injection of CFA induced a rather similar pattern of inflammatory pain in 3-month-old CRND8 mice and their wild-type littermates, recovery from inflammatory pain seemed faster in 12-month-old CRND8 mice than wild-type mice. These findings suggest that APP and Aβ peptides suppress both nociception and inflammatory pain and are likely involved in blunt pain perception of Alzheimer's patients in clinical settings.
authors.affiliation: Douglas Mental Health University Institute, Montreal, Quebec, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Shukla
authors.forename: R
authors.initials: R
authors.lastname: Quirion
authors.forename: W
authors.initials: W
authors.lastname: Ma
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D015153:Blotting, Western; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D005620:Freund's Adjuvant; D006358:Hot Temperature; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000523:psychology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010146:Pain / Q000378:metabolism* / Q000523:psychology*; D010812:Physical Stimulation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013373:Substance P / Q000378:metabolism; D050916:TRPV Cation Channels / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D013373:Substance P; D005620:Freund's Adjuvant; D015740:Calcitonin Gene-Related Peptide
keywords: 3,3′-diaminobenzidine; AD; APP; Alzheimer’s disease; Aβ; CFA; CGRP; CRND8 transgenic mice; DAB; DRG; IB4; NGS; PB; PBS; PWL; PWT; SP; TBS; TBS+T; TRPV1; Tris buffered saline; Tris-buffered saline containing 0.05% Tween-20; VR1; amyloid precursor protein; calcitonin gene-related peptide; complete Freud’s adjuvant; dorsal root ganglion; i.pl.; inflammatory pain; intraplantar; isolectin-4; nociception; normal goat serum; paw withdrawal latency; paw withdrawal threshold; phosphate buffer; phosphate-buffered saline; substance P; transient receptor potential vallinoid-1; vallinoid receptor 1; β-amyloid