Interleukin-1β and Glutamate Activate the NF-κB/Rel Binding Site from the Regulatory Region of the Amyloid Precursor Protein Gene in Primary Neuronal Cultures

Abstract

We originally reported that members of the family of transcription factors NF-B/Rel can specifically recognize two identical sequences, referred to as APP B sites, which are present in the 5 -regulatory region of the APP gene. Here we show that the APP B sites interact specifically with a complex which contains one of the subunits of the family, defined as p50 protein, and that they act as positive modulators of gene transcription in cells of neural origin. Additionally, the nuclear complex specifically binding to the APP B sites is constitutively expressed in primary neurons from rat cerebellum and it is up-regulated in response to both the inflammatory cytokine interleukin-1␤ (IL-1␤) and the excitatory amino acid glutamate. Since IL-1, whose levels are known to be induced in brain of individuals affected by Alzheimer's disease, and glutamate, are stimuli which have been regarded as major actors on the stage of neurodegenerative processes, we believe our evidence as potentially relevant for understanding the neuropathology associated with Alzheimer's disease.Alzheimer's disease (AD) 1 is a neurodegenerative disorder characterized by abnormal deposition of extracellular congophilic plaques in the brain. The main constituent of plaques is a 39-to 43-amino acid peptide, named ␤-amyloid, which is a proteolytic fragment of the amyloid precursor protein (APP) (1). In recent years, most experimental studies have been aimed at understanding the mechanisms of ␤-amyloid formation and deposition and at identifying potential risk factors which may favor these processes. In particular, APP gene mutations occurring in families with Familial AD have been correlated with disturbance in protein processing, which in turn, may predispose to ␤ amyloid formation (2, 3). However, since APP gene mutations represent a minor percentage of AD cases, it is evident that other mechanisms may exist to account for ␤-amyloid deposition. In this regard, it should not be underestimated that overexpression of the APP gene may be involved in the pathogenetic mechanisms of amyloid formation, at least in some clinical forms of the disease. Several observations underscore the potential contribution of the APP gene overexpression to favoring AD neuropathology: (i) the marked accumulation of ␤-amyloid which correlates with increased levels of APP mRNA in trisomy 21 (Down's syndrome) (4); (ii) the increased levels of APP gene transcripts in specific areas of the AD brains (5-7); (iii) the increased APP mRNA transcription in cultured fibroblasts from the Familial Alzheimer's disease-1 family (8). In addition, post-mitotic neurons which overexpress full-length APP were shown to degenerate and accumulate large amounts of amyloidogenic C-terminal fragments (9). The promoter region of the APP gene (10) has been shown to contain binding sequences for several known transcription factors (11)(12)(13)(14)(15)(16)(17)(18)(19). We reported recently (20) that a novel regulatory pathway for APP gene control at the transcriptional level may involve members of the NF...

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