title: Neuregulin-1 and erbB4 immunoreactivity is associated with neuritic plaques in Alzheimer disease brain and in a transgenic model of Alzheimer disease.
abstract: Neuregulin-1 (NRG-1) regulates developmental neuronal survival and synaptogenesis, astrocytic differentiation, and microglial activation. Given these NRG-1 actions, we hypothesized that the synaptic loss, gliosis, inflammation, and neuronal death occurring in Alzheimer disease (AD) is associated with altered expression of NRG-1 and its receptors (the erbB2, erbB3, and erbB4 membrane tyrosine kinases). We examined the expression and distribution of NRG-1 and the erbB kinases in the hippocampus of AD patients and cognitively normal controls and in transgenic mice that coexpress AD-associated mutations of the beta amyloid precursor protein (APP(K670N,M671L)) and presenilin-1 (PS1(M146L)). In the hippocampi of both control humans and wild type mice, NRG-1 and the 3 erbB receptors are expressed in distinct cellular compartments of hippocampal neurons. All 4 molecules are associated with neuronal cell bodies, but only NRG-1, erbB2, and erbB4 are present in synapse-rich regions. In AD and in the doubly transgenic mouse, erbB4 is expressed by reactive astrocytes and microglia surrounding neuritic plaques. In AD brains, microglia and, to a lesser extent, dystrophic neurites, also upregulate NRG-1 in neuritic plaques, suggesting that autocrine and/or paracrine interactions regulate NRG-1 action within these lesions. NRG-1 and erbB4, as well as erbB2, are similarly associated with neuritic plaques in the doubly transgenic mice. Thus, in AD the hippocampal distribution of NRG-1 and erbB4 is altered. The similarities between the alterations in the expression of NRG-1 and its receptors in human AD and in APP(K670N;M671L)/PS1(M146L) mutant mice suggests that this animal model may be very informative in deciphering the potential role of these molecules in AD.
authors.affiliation: Department of Pathology, The University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA.
authors.forename: Abhik Ray
authors.initials: AR
authors.lastname: Chaudhury
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Gerecke
authors.forename: J Michael
authors.initials: JM
authors.lastname: Wyss
authors.forename: David G
authors.initials: DG
authors.lastname: Morgan
authors.forename: Marcia N
authors.initials: MN
authors.lastname: Gordon
authors.forename: Steven L
authors.initials: SL
authors.lastname: Carroll
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D066246:ErbB Receptors / Q000032:analysis* / Q000096:biosynthesis; D005260:Female; D006624:Hippocampus / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007120:Immunochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020890:Neuregulin-1 / Q000032:analysis* / Q000096:biosynthesis; D058225:Plaque, Amyloid / Q000737:chemistry* / Q000378:metabolism; D066247:Receptor, ErbB-4
chemical_list: D020890:Neuregulin-1; C587689:ERBB4 protein, human; D066246:ErbB Receptors; C587690:Erbb4 protein, mouse; D066247:Receptor, ErbB-4