The sporadic nature of Alzheimer's disease (AD) argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead (Pb) during brain development predetermined the expression and regulation of the amyloid precursor protein (APP) and its amyloidogenic ␤-amyloid (A␤) product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 (␤-site APP cleaving enzyme 1)] as well as their transcriptional regulator (Sp1) were elevated in aged (23-year-old) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of A␤ staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD.

Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.

Neurobiological disorders have diverse manifestations and symptomology. Neurodegenerative disorders such as Alzheimer’s disease (AD) manifest late in life and are characterized by, among other symptoms, progressive loss of synaptic markers. Developmental disorders, such as autism spectrum, appear in childhood. Neuropsychiatric and affective disorders, such as schizophrenia and major depressive disorder, respectively, have broad ranges of age of onset and symptoms. However, all share uncertain etiologies, with opaque relationships between genes and environment. We propose a “Latent Early–life Associated Regulation” (LEARn) model, positing latent changes in expression of specific genes initially primed at the developmental stage of life. In this model, environmental agents epigenetically disturb gene regulation in a long–term fashion, beginning at early developmental stages, but these perturbations might not have pathological results until significantly later in life. The LEARn model operates through the regulatory region (promoter) of the gene, specifically through changes in methylation and oxidation status within the promoter of specific genes. The LEARn model combines genetic and environmental risk factors in an epigenetic pathway to explain the etiology of the most common, i.e., sporadic, forms of neurobiological disorders.

The first step in the generation of the amyloid-beta peptide (Abeta) deposited in the brains of patients with Alzheimer's disease (AD) is the processing of the larger Abeta precursor protein (APP) by an integral membrane aspartyl protease named the beta-site APP-cleaving enzyme (BACE). We present the genomic organization of the BACE gene. BACE mRNAs are synthesized as nine exons and eight introns from a 30.6 kb region of chromosome 11q23.2-11q23.3. Regulation of BACE may play an important role in regulating the levels of Abeta produced and is therefore likely to play an important role in AD. Herein, we report the cloning and detailed analysis of 3765 nucleotides of the promoter region of BACE and 364 nucleotides of the 5' untranslated region of the BACE mRNA (5' UTR). Characteristic "CAAT" and "TATA" boxes are absent within 1.5 kb of the transcription start site (TSS). The promoter region and 5' UTR contain multiple transcription factor binding sites, such as activator protein (AP)1, AP2, cAMP response element binding protein (CREB), estrogen responsive element (ERE), glucocorticoid responsive element (GRE), "GC" box, nuclear factor (NF)-kappaB, signal transducer and activator of transcription (STAT)1, stimulating protein (SP)1, metal-regulatory elements, and possible Zeste binding sites. Limited interspecies similarity was observed between the human sequence and corresponding genomic DNA from the rat and mouse sequences, but several transcription factor-binding sites are conserved. Thus, the BACE gene contains basal regulatory elements, inducible features and sites for regulated activity by various transcription factors. These results identify the important regions for functional analysis of the binding domains and neuron-specific expression (1). Such a study will allow us to further examine the possible role of changes in the promoter of BACE in AD pathogenesis.

Major characteristics of Alzheimer's disease (AD) are synaptic loss, cholinergic dysfunction, and abnormal protein depositions in the brain. The amyloid ␤-peptide (A␤), a proteolytic fragment of amyloid ␤ precursor protein (APP), aggregates to form neuritic plaques and has a causative role in AD. A present focus of AD research is to develop safe A␤-lowering drugs. A selective acetylcholinesterase inhibitor, phenserine, in current human trials lowers both APP and A␤. Phenserine is dose-limited in animals by its cholinergic actions; its cholinergically inactive enantiomer, posiphen (ϩ)-[phenserine], was assessed. In cultured human neuroblastoma cells, posiphen, like phenserine, dose-and time-dependently lowered APP and A␤ levels by reducing the APP synthesis rate. This action translated to an in vivo system. Posiphen administration to mice (7.5-75 mg/kg daily, 21 consecutive days) significantly decreased levels of total APP (tissue mass-adjusted) in a dose-dependent manner. A␤ 40 and A␤ 42 levels were significantly lowered by posiphen (Ն15 mg/kg) compared with controls. The activities of ␣-, ␤-, and ␥-secretases were assessed in the same brain samples, and ␤-secretase activity was significantly reduced. Posiphen, like phenserine, can lower A␤ via multiple mechanisms and represents an interesting drug candidate for AD treatment.Alzheimer's disease (AD) is typified by progressive impairment in short-term memory and emotional disturbances that result from dysfunction and death of neurons in the hippocampus and associated regions of the limbic system and cerebral cortex. These aberrations are considered to result, in part, from microtubule-associated protein () tangles and abnormal aggregates of cytoskeletal proteins (Cairns et al., 2004), oxidative stress, and the overproduction and accumulation of amyloid-␤ peptide (A␤) in and surrounding neurons (Selkoe, 2005).This 39-to 43-amino acid peptide (molecular mass ϳ4.1 kDa) is a core constituent of amyloid plaques and results from two catalytic cleavages of the larger integral membrane protein, amyloid-␤ precursor protein (APP; ϳ110 -130 kDa), at the N terminus (␤-secretase) and C terminus (␥-secretase) of A␤ (Sambamurti et al., 2002;Lahiri et al., 2003b;Selkoe, 2005). Significant evidence indicates that A␤ changes conformation from a physiological to a pathological, fibrillar peptide form, which not only induces local structural disruption of synapses and neurite breakage but also results in cell death due to perturbed calcium homeostasis and oxidative stress. In addition, soluble aggregates of A␤ or A␤-derived diffusible ligands found in the brains of AD patients have been recently shown to target synapses (Gong et al., 2003) and play a role in inhibiting LTP (Walsh et al., 2002;LaFerla and Oddo, 2005). Conjointly, these studies point to the importance of A␤ in learning and memory, suggest a causative role of A␤ in AD pathophysiology, and thereby support its

Alzheimer's disease is characterized by the accumulation of amyloid-␤ peptide, which is cleaved from the amyloid-␤ precursor protein (APP). Reduction in levels of the potentially toxic amyloid-␤ has emerged as one of the most important therapeutic goals in Alzheimer's disease. Key targets for this goal are factors that affect the regulation of the APP gene. Recent in vivo and in vitro studies have illustrated the importance of copper in Alzheimer's disease neuropathogenesis and suggested a role for APP and amyloid-␤ in copper homeostasis. We hypothesized that metals and in particular copper might alter APP gene expression. To test the hypothesis, we utilized human fibroblasts overexpressing the Menkes protein (MNK), a major mammalian copper efflux protein. MNK deletion fibroblasts have high intracellular copper, whereas MNK overexpressing fibroblasts have severely depleted intracellular copper. We demonstrate that copper depletion significantly reduced APP protein levels and down-regulated APP gene expression. Furthermore, APP promoter deletion constructs identified the copper-regulatory region between ؊490 and ؉104 of the APP gene promoter in both basal MNK overexpressing cells and in copper-chelated MNK deletion cells. Overall these data support the hypothesis that copper can regulate APP expression and further support a role for APP to function in copper homeostasis. Copper-regulated APP expression may also provide a potential therapeutic target in Alzheimer's disease.

Autism is characterized by restricted, repetitive behaviors and impairment in socialization and communication. Although no neuropathologic substrate underlying autism has been found, the findings of brain overgrowth via neuroimaging studies and increased levels of brain-derived neurotrophic factor (BDNF) in neuropathologic and blood studies favor an anabolic state. We examined acetylcholinesterase, plasma neuronal proteins, secreted beta-amyloid precursor protein (APP), and amyloid-beta 40 and amyloid-beta 42 peptides in children with and without autism. Children with severe autism and aggression expressed secreted beta-amyloid precursor protein at two or more times the levels of children without autism and up to four times more than children with mild autism. There was a trend for children with autism to show higher levels of secreted beta-amyloid precursor protein and nonamyloidogenic secreted beta-amyloid precursor protein and lower levels of amyloid-beta 40 compared with controls. This favors an increased alpha-secretase pathway in autism (anabolic), opposite to what is seen in Alzheimer disease. Additionally, a complex relationship between age, acetylcholinesterase, and plasma neuronal markers was found.

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