Galantamine, a drug for Alzheimer’s disease, is a novel cholinergic agent with a dual mode of action, which inhibits acetylcholinesterase and allosterically modulates nicotinic acetylcholine receptors (nAChRs), as a result stimulates catecholamine neurotransmission. In the present study, we investigated whether galantamine exerts cognitive improving effects through the allosteric modulation of nAChR in the intracerebroventricular beta amyloid (Aβ)₂₅₋₃₅-injected animal model of Alzheimer’s disease. Galantamine (3 mg/kg p.o.) significantly increased the extracellular dopamine release in the hippocampus of saline- and Aβ₂₅₋₃₅-injected mice. The effects of nicotine on the extracellular dopamine release were potentiated by galantamine, but antagonized by mecamylamine, a nAChR antagonist. Aβ₂₅₋₃₅-injected mice, compared with saline-injected mice, could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting Aβ₂₅₋₃₅ induced cognitive impairment. Galantamine improved the Aβ₂₅₋₃₅-induced cognitive impairment in the novel object recognition and fear-conditioning tasks. These improving effects of galantamine were blocked by the treatment with mecamylamine, SCH-23390, a dopamine-D1 receptor antagonist, and sulpiride, a dopamine-D2 receptor antagonist, but not by scopolamine, a muscarinic acetylcholine receptor antagonist. This study provides the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus through the allosteric potentiation of nAChRs. The improving-effects of galantamine on the Aβ₂₅₋₃₅-induced cognitive impairment may be mediated through the activation of, at least in part, dopaminergic systems, and the enhancement of dopamine release may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.

Progressive decrease in neuronal function is an established feature of Alzheimer's disease (AD). Previous studies have shown that amyloid β (Aβ) peptide induces acute increase in spontaneous synaptic activity accompanied by neurotoxicity, and Aβ induces excitotoxic neuronal death by increasing calcium influx mediated by hyperactive α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazole propionate (AMPA) receptors. An in vivo study has revealed subpopulations of hyperactive neurons near Aβ plaques in mutant amyloid precursor protein (APP)‐transgenic animal model of Alzheimer's disease (AD) that can be normalized by an AMPA receptor antagonist. In the present study, we aim to determine whether soluble Aβ acutely induces hyperactivity of AMPA receptors by a mechanism involving β ₂ adrenergic receptor (β ₂ AR). We found that the soluble Aβ binds to β ₂ AR, and the extracellular N terminus of β ₂ AR is critical for the binding. The binding is required to induce G‐protein/cAMP/protein kinase A (PKA) signaling, which controls PKA‐dependent phosphorylation of GluR1 and β ₂ AR, and AMPA receptor‐mediated excitatory postsynaptic currents (EPSCs). β ₂ AR and GluR1 also form a complex comprising postsynaptic density protein 95 (PSD95), PKA and its anchor AKAP150, and protein phosphotase 2A (PP2A). Both the third intracellular (i3) loop and C terminus of β ₂ AR are required for the β ₂ AR/AMPA receptor complex. Aβ acutely induces PKA phosphorylation of GluR1 in the complex without affecting the association between two receptors. The present study reveals that non‐neurotransmitter Aβ has a binding capacity to β ₂ AR and induces PKA‐dependent hyperactivity in AMPA receptors.—Wang, D., Govindaiah, G., Liu, R., De Arcangelis, V., Cox, C. L., Xiang, Y. K. Binding of amyloid β peptide to β ₂ adrenergic receptor induces PKA‐dependent AMPA receptor hyperactivity. FASEB J . 24, 3511–3521 (2010). www.fasebj.org

Alzheimer disease (AD) is characterized by neurodegeneration marked by loss of synapses and spines associated with hyperphosphorylation of tau protein. Accumulating amyloid β peptide (Aβ) in brain is linked to neurofibrillary tangles composed of hyperphosphorylated tau in AD. Here, we identify β₂-adrenergic receptor (β₂AR) that mediates Aβ-induced tau pathology. In the prefrontal cortex (PFC) of 1-year-old transgenic mice with human familial mutant genes of presenilin 1 and amyloid precursor protein (PS1/APP), the phosphorylation of tau at Ser-214 Ser-262 and Thr-181, and the protein kinases including JNK, GSK3α/β, and Ca²⁺/calmodulin-dependent protein kinase II is increased significantly. Deletion of the β₂AR gene in PS1/APP mice greatly decreases the phosphorylation of these proteins. Further analysis reveals that in primary PFC neurons, Aβ signals through a β₂AR-PKA-JNK pathway, which is responsible for most of the phosphorylation of tau at Ser-214 and Ser-262 and a significant portion of phosphorylation at Thr-181. Aβ also induces a β₂AR-dependent arrestin-ERK1/2 activity that does not participate in phosphorylation of tau. However, inhibition of the activity of MEK, an upstream enzyme of ERK1/2, partially blocks Aβ-induced tau phosphorylation at Thr-181. The density of dendritic spines and synapses is decreased in the deep layer of the PFC of 1-year-old PS1/APP mice, and the mice exhibit impairment of learning and memory in a novel object recognition paradigm. Deletion of the β₂AR gene ameliorates pathological effects in these senile PS1/APP mice. The study indicates that β₂AR may represent a potential therapeutic target for preventing the development of AD.

Emerging evidence indicates that amyloid β peptide (Aβ) initially induces subtle alterations in synaptic function in Alzheimer disease. We have recently shown that Aβ binds to β₂ adrenergic receptor (β₂AR) and activates protein kinase A (PKA) signaling for glutamatergic regulation of synaptic activities. Here we show that in the cerebrums of mice expressing human familial mutant presenilin 1 and amyloid precursor protein genes, the levels of β₂AR are drastically reduced. Moreover, Aβ induces internalization of transfected human β₂AR in fibroblasts and endogenous β₂AR in primary prefrontal cortical neurons. In fibroblasts, Aβ treatment also induces transportation of β₂AR into lysosome, and prolonged Aβ treatment causes β₂AR degradation. The Aβ-induced β₂AR internalization requires the N terminus of the receptor containing the peptide binding sites and phosphorylation of β₂AR by G protein-coupled receptor kinase, not by PKA. However, the G protein-coupled receptor kinase phosphorylation of β₂AR and the receptor internalization are much slower than that induced by βAR agonist isoproterenol. The Aβ-induced β₂AR internalization is also dependent on adaptor protein arrestin 3 and GTPase dynamin, but not arrestin 2. Functionally, pretreatment of primary prefrontal cortical neurons with Aβ induces desensitization of β₂AR, which leads to attenuated response to subsequent stimulation with isoproterenol, including decreased cAMP levels, PKA activities, PKA phosphorylation of serine 845 on α-amino-2,3-dihydro-5-methyl-3-oxo-4-isoxazolepropanoic acid (AMPA) receptor subunit 1 (GluR1), and AMPA receptor-mediated miniature excitatory postsynaptic currents. This study indicates that Aβ induces β₂AR internalization and degradation leading to impairment of adrenergic and glutamatergic activities.

Diabetes is a metabolic disease that raises the risk of microvascular and neurological disorders. Insensitivity to insulin is a characteristic of type II diabetes, which accounts for 85-90 percent of all diabetic patients. The fundamental molecular factor of insulin resistance may be impaired cell signal transduction mediated by the insulin receptor (IR). Several cell-signaling proteins, including IR, insulin receptor substrate (IRS), and phosphatidylinositol 3-kinase (PI3K), have been recognized as being important in the impaired insulin signaling pathway since they are associated with a large number of proteins that are strictly regulated and interact with other signaling pathways. Many studies have found a correlation between IR alternative splicing, IRS gene polymorphism, the complicated regulatory function of IRS serine/threonine phosphorylation, and the negative regulatory role of p85 in insulin resistance and diabetes mellitus. This review brings up-to-date knowledge of the roles of signaling proteins in insulin resistance in order to aid in the discovery of prospective targets for insulin resistance treatment.