Type 2 (T2) diabetes mellitus (DM) has been associated with an increased incidence of neurodegenerative disorders, including Alzheimer's disease (AD). Several pathological features are shared between diabetes and AD, including dysfunctional insulin signaling and a dysregulation of glucose metabolism. It has therefore been suggested that not only may the two conditions share specific molecular mechanisms but also that agents with proven efficacy in one may be useful against the other. Hence, the present study characterized the effects of a clinically approved long-acting analogue, exendin-4 (Ex-4), of the endogenous insulin releasing incretin, glucagon-like peptide-1 (GLP-1), on stress-induced toxicity in neuronal cultures and on amyloid-beta protein (Abeta) and tau levels in triple transgenic AD (3xTg-AD) mice with and without streptozocin (STZ)-induced diabetes. Ex-4 ameliorated the toxicity of Abeta and oxidative challenge in primary neuronal cultures and human SH-SY5Y cells in a concentration-dependent manner. When 11 to 12.5 month old female 3xTg AD mice were challenged with STZ or saline, and thereafter treated with a continuous subcutaneous infusion of Ex-4 or vehicle, Ex-4 ameliorated the diabetic effects of STZ in 3xTg-AD mice, elevating plasma insulin and lowering both plasma glucose and hemoglobin A1c (HbA1c) levels. Furthermore, brain levels of Abeta protein precursor and Abeta, which were elevated in STZ 3xTg-AD mice, were significantly reduced in Ex-4 treated mice. Brain tau levels were unaffected following STZ challenge, but showed a trend toward elevation that was absent following Ex-4 treatment. Together, these results suggest a potential value of Ex-4 in AD, particularly when associated with T2DM or glucose intolerance.

BackgroundNeuroinflammation is associated with virtually all major neurodegenerative disorders, including Alzheimer’s disease (AD). Although it remains unclear whether neuroinflammation is the driving force behind these disorders, compelling evidence implicates its role in exacerbating disease progression, with a key player being the potent proinflammatory cytokine TNF-α. Elevated TNF-α levels are commonly detected in the clinic and animal models of AD.MethodsThe potential benefits of a novel TNF-α-lowering agent, 3,6′-dithiothalidomide, were investigated in cellular and rodent models of neuroinflammation with a specific focus on AD. These included central and systemic inflammation induced by lipopolysaccharide (LPS) and Aβ1–42 challenge, and biochemical and behavioral assessment of 3xTg-AD mice following chronic 3,6′-dithiothaliodmide.Results3,6′-Dithiothaliodmide lowered TNF-α, nitrite (an indicator of oxidative damage) and secreted amyloid precursor protein (sAPP) levels in LPS-activated macrophage-like cells (RAW 264.7 cells). This translated into reduced central and systemic TNF-α production in acute LPS-challenged rats, and to a reduction of neuroinflammatory markers and restoration of neuronal plasticity following chronic central challenge of LPS. In mice centrally challenged with Aβ1–42 peptide, prior systemic 3,6′-dithiothalidomide suppressed Aβ-induced memory dysfunction, microglial activation and neuronal degeneration. Chronic 3,6′-dithiothalidomide administration to an elderly symptomatic cohort of 3xTg-AD mice reduced multiple hallmark features of AD, including phosphorylated tau protein, APP, Aβ peptide and Aβ-plaque number along with deficits in memory function to levels present in younger adult cognitively unimpaired 3xTg-AD mice. Levels of the synaptic proteins, SNAP25 and synaptophysin, were found to be elevated in older symptomatic drug-treated 3xTg-AD mice compared to vehicle-treated ones, indicative of a preservation of synaptic function during drug treatment.ConclusionsOur data suggest a strong beneficial effect of 3,6′-dithiothalidomide in the setting of neuroinflammation and AD, supporting a role for neuroinflammation and TNF-α in disease progression and their targeting as a means of clinical management.

The aryl hydrocarbon receptor (AHR) is a nuclear receptor that modulates the response to environmental stimuli. It was recognized historically for its role in toxicology but, in recent decades, it has been increasingly recognized as an important modulator of disease—especially for its role in modulating immune and inflammatory responses. AHR has been implicated in many diseases that are driven by immune/inflammatory processes, including major depressive disorder, multiple sclerosis, rheumatoid arthritis, asthma, and allergic responses, among others. The mechanisms by which AHR has been suggested to impact immune/inflammatory diseases include targeted gene expression and altered immune differentiation. It has been suggested that single nucleotide polymorphisms (SNPs) that are near AHR-regulated genes may contribute to AHR-dependent disease mechanisms/pathways. Further, we have found that SNPs that are outside of nuclear receptor binding sites (i.e., outside of AHR response elements (AHREs)) may contribute to AHR-dependent gene regulation in a SNP- and ligand-dependent manner. This review will discuss the evidence and mechanisms of AHR contributions to immune/inflammatory diseases and will consider the possibility that SNPs that are outside of AHR binding sites might contribute to AHR ligand-dependent inter-individual variation in disease pathophysiology and response to pharmacotherapeutics.

Background: Expression of amyloid-␤ (A␤) precursor protein (APP), implicated in Alzheimer disease (AD), is regulated by complex mechanisms involving microRNAs. Results: miR-153 reduces APP and A␤ in human brain cultures and is dysregulated in AD. Conclusion: miR-153 physiologically regulates human APP expression and A␤ and may contribute to AD pathoetiology. Significance: miR-153 is a potential novel drug target in AD.

Autism is a neurodevelopmental disorder characterized by deficits in verbal communication, social interactions, and the presence of repetitive, stereotyped and compulsive behaviors. Excessive early brain growth is found commonly in some patients and may contribute to disease phenotype. Reports of increased levels of brain-derived neurotrophic factor (BDNF) and other neurotrophic-like factors in autistic neonates suggest that enhanced anabolic activity in CNS mediates this overgrowth effect. We have shown previously that in a subset of patients with severe autism and aggression, plasma levels of the secreted amyloid-β (Aβ) precursor protein-alpha form (sAPPα) were significantly elevated relative to controls and patients with mild-to-moderate autism. Here we further tested the hypothesis that levels of sAPPα and sAPPβ (proteolytic cleavage products of APP by α- and β-secretase, respectively) are deranged in autism and may contribute to an anabolic environment leading to brain overgrowth. We measured plasma levels of sAPPα, sAPPβ, Aβ peptides and BDNF by corresponding ELISA in a well characterized set of subjects. We included for analysis 18 control, 6 mild-to-moderate, and 15 severely autistic patient plasma samples. We have observed that sAPPα levels are increased and BDNF levels decreased in the plasma of patients with severe autism as compared to controls. Further, we show that Aβ1-40, Aβ1-42, and sAPPβ levels are significantly decreased in the plasma of patients with severe autism. These findings do not extend to patients with mild-to-moderate autism, providing a biochemical correlate of phenotypic severity. Taken together, this study provides evidence that sAPPα levels are generally elevated in severe autism and suggests that these patients may have aberrant non-amyloidogenic processing of APP.

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-␤ peptide (A␤), A␤ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted ␣ form of the amyloid-␤ precursor protein (sAPP␣) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPP␣ levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPP␣ level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPP␣ and production of insoluble A␤ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. Neurology ® 2011;76:1344-1352 GLOSSARY A␤ ϭ amyloid-␤; AD ϭ Alzheimer disease; APP ϭ A␤ precursor protein; FMRP ϭ fragile X mental retardation protein; FXS ϭ fragile X syndrome; FXTAS ϭ fragile X-associated tremor/ataxia syndrome; LEARn ϭ latent early-life associated regulation; LTD ϭ long-term depression; LTP ϭ long-term potentiation; mGluR5 ϭ metabotropic glutamate receptor 5; sAPP␣ ϭ secreted ␣ form of the amyloid-␤ precursor protein; UTR ϭ untranslated region.There is growing interest in associations between neurodevelopmental and neuropsychiatric disorders across the lifespan. Case in point is the association drawn between fragile X syndrome (FXS) and fragile X-associated tremor/ataxia syndrome (FXTAS) found in subsets of older adults harboring fragile X mental retardation 1 gene (FMR1) premutations.1 FXS is the most common inherited form of intellectual disability.2,3 FXTAS is a condition of progressive tremor and ataxia in individuals who show no premorbid cognitive deficits, developing over the age of 50. Dementia occurs in a subset of those with FXTAS. Macrocephaly is seen in children with FXS, 4 as discussed below, and brain atrophy in the cerebrum, brainstem, and cerebellum is seen in FXTAS. References e1-e45 are available on the Neurology Web site at www.neurology.org.

Background: BACE1 is the rate-limiting enzyme in the synthesis of A␤ from amyloid precursor protein.Results: Human miR-339-5p negatively regulates BACE1 and A␤ in human brain cultures and is reduced in AD specimens. Conclusion: Human miR-339-5p physiologically regulates human BACE1 protein expression and A␤ and is dysregulated in the AD brain. Significance: miR-339-5p represents a novel drug target in AD.

Memantine is a moderate-affinity, uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist that stabilizes cognitive, functional, and behavioral decline in patients with moderate to severe Alzheimer's disease (AD). In AD, the extracellular deposition of fibrillogenic amyloid-beta peptides (Aβ) occurs due to aberrant processing of the full-length Aβ precursor protein (APP). Memantine protects neurons from the neurotoxic effects of Aβ and improves cognition in transgenic mice with high brain levels of Aβ. However, it is unknown how memantine protects cells against neurodegeneration and affects APP processing and Aβ production. We report the effects of memantine in three different systems. In human neuroblastoma cells, memantine, at therapeutically relevant concentrations (1-4 μM), decreased levels of secreted APP and Aβ . Levels of the potentially amylodogenic Aβ 1-42 were undetectable in these cells. In primary rat cortical neuronal cultures, memantine treatment lowered Aβ 1-42 secretion. At the concentrations used, memantine treatment was not toxic to neuroblastoma or primary cultures and increased cell viability and/or metabolic activity under certain conditions. In APP/presenilin-1 (PS1) transgenic mice exhibiting high brain levels of Aβ 1-42 , oral dosing of memantine (20 mg/kg/day for 8 days) produced plasma drug concentration of 0.96 μM and significantly reduced the cortical levels of soluble Aβ . The ratio of Aβ 1-40 /Aβ 1-42 increased in treated mice, suggesting effects on the γ-secretase complex. Thus, memantine reduces the levels of Aβ peptides at therapeutic concentrations and may inhibit the accumulation of fibrillogenic Aβ in mammalian brains. Memantine's ability to preserve neuronal cells against neurodegeneration, increase metabolic activity, and lower Aβ level has therapeutic implications for neurodegenerative disorders. KeywordsAging; cortex; dementia; lysosome; membrane; tissue culture; memory In Alzheimer's disease (AD), a gradual impairment in short-term memory and cognition results from the dysfunction and death of neurons in the hippocampus, limbic system, and cerebral cortex (Goedert and Spillantini, 2006;Tanzi and Bertram, 2008). AD is characterized by brain * Contributed equally ** Corresponding author: Debomoy K. Lahiri, PhD, Department of Psychiatry, Indiana University School of Medicine, 791 Union Drive, Indianapolis, USA, Tel: (317) 274-2706; Fax: (317) NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript depositions of amyloid plaques and neurofibrillary tangles, loss of the synaptophysin protein, and deficits in cholinergic neurotransmission (Giacobini, 2003;Lahiri et al., 2003;Reinhard et al., 2005;Selkoe, 2005). These aberrations are believed to result, in part, from oxidative stress, membrane damage, and the over-production and accumulation of amyloid-β peptide (Aβ), a 39-43 amino acid polypeptide that is a core constituent of amyloid plaques (Dumery et al., 2001;Sambamurti et al., 2006). Two Aβ peptides predominate in brain tissue, one i...