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.

Modulation of Gene Expression and Cytoskeletal Dynamics by the Amyloid Precursor Protein Intracellular Domain (AICD)

“…Furthermore, other groups have also reported differential expression of PRKC (Par-4) (El Guendy and Rangnekar, 2003) and TPM1 (Galloway et al, 1990) in AD brain samples compared with brains from unaffected patients. Moreover, neuritic plaques positive for neuregulin (Chaudhury et al, 2003) and fibronectin 1 (Van Gool et al, 1994) have been shown by immunohistochemistry. Given that several of our AICD target genes have previously demonstrated differential expression levels during AD progression, it is interesting to postulate that increased expression of AICD, and of its targets, might play an important role in AD.…”

Expression analysis of neuregulin-1 in the dorsolateral prefrontal cortex in schizophrenia

“…27 Little is known about NRG-1 expression in human brain; however, NRG-1 is present in neuronal cell bodies and synapse-rich regions in the hippocampus and type II isoform is expressed in oligodendrocytes, astrocytes, and microglia. 28,29 We detected mRNA of each of the three major classes of NRG-1 isoforms in human DLPFC, but we did not characterize the multiple spice variants within these isoforms. We also found a positive correlation between expression levels of each of the NRG-1 isoforms with age in normal subjects, suggesting that NRG-1 mRNA increases as the prefrontal cortex ages.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…In the brains of patients with Alzheimer's disease, neuregulin-1 is upregulated in neuritic plaques, suggesting a role for ErbB signaling in the disease [140]. Accumulation of unprocessed neuregulin-1 and defective myelination occurs within cells lacking β-amyloid cleaving enzyme-1 (BACE1), an enzyme thought important in the pathophysiology of the Alzheimer's disease [141].…”