Microglial activation is an important pathological component in brains of patients with Alzheimer’s disease (AD), and fibrillar amyloid-β (Aβ) peptides play an important role in microglial activation in AD. However, mechanisms by which Aβ peptides induce the activation of microglia are poorly understood. The present study underlines the importance of TLR2 in mediating Aβ peptide-induced activation of microglia. Fibrillar Aβ1–42 peptides induced the expression of inducible NO synthase, proinflammatory cytokines (TNF-α, IL-1β, and IL-6), and integrin markers (CD11b, CD11c, and CD68) in mouse primary microglia and BV-2 microglial cells. However, either antisense knockdown of TLR2 or functional blocking Abs against TLR2 suppressed Aβ1–42-induced expression of proinflammatory molecules and integrin markers in microglia. Aβ1–42 peptides were also unable to induce the expression of proinflammatory molecules and increase the expression of CD11b in microglia isolated from TLR2−/− mice. Finally, the inability of Aβ1–42 peptides to induce the expression of inducible NO synthase and to stimulate the expression of CD11b in vivo in the cortex of TLR2−/− mice highlights the importance of TLR2 in Aβ-induced microglial activation. In addition, ligation of TLR2 alone was also sufficient to induce microglial activation. Consistent to the importance of MyD88 in mediating the function of various TLRs, antisense knockdown of MyD88 also inhibited Aβ1–42 peptide-induced expression of proinflammatory molecules. Taken together, these studies delineate a novel role of TLR2 signaling pathway in mediating fibrillar Aβ peptide-induced activation of microglia.

Daily living often requires individuals to flexibly respond to new circumstances. There is considerable evidence that the striatum is part of a larger neural network that supports flexible adaptations. Cholinergic interneurons are situated to strongly influence striatal output patterns which may enable flexible adaptations. The present experiments investigated whether acetylcholine actions in different striatal regions support behavioral flexibility by measuring acetylcholine efflux during place reversal learning. Acetylcholine efflux selectively increased in the dorsomedial striatum, but not dorsolateral or ventromedial striatum during place reversal learning. In order to modulate the M2-class of autoreceptors, administration of oxotremorine sesquifumurate (100 nM) into the dorsomedial striatum, concomitantly impaired reversal learning and an increase in acetylcholine output. These effects were reversed by the m 2 muscarinic receptor antagonist, AF-DX-116 (20 nM). The effects of oxotremorine sesquifumurate and AF-DX-116 on acetylcholine efflux were selective to behaviorally-induced changes as neither treatment affected acetylcholine output in a resting condition. In contrast to reversal learning, acetylcholine efflux in the dorsomedial striatum did not change during place acquisition. The results reveal an essential role for cholinergic activity and define its locus of control to the dorsomedial striatum in cognitive flexibility.

No abstract

Despite being a proinflammatory cytokine, tumor necrosis factor-α (TNF-α) preconditions neurons against various toxic insults. However, underlying molecular mechanisms are poorly understood. The present study identifies the importance of CREB-binding protein (CBP) in facilitating TNF-α-mediated preconditioning in neurons. Treatment of rat primary neurons with fibrillar amyloid-β 1–42 (Aβ) resulted in the loss of CBP protein. However, this loss was compensated by TNF-α preconditioning as the expression of neuronal CBP was upregulated in response to TNF-α treatment. The induction of CBP by TNF-α was observed only in neurons, but not in astroglia and microglia, and it was contingent on the activation of transcription factor NF-κB. Interestingly, antisense knockdown of CBP abrogated TNF-α-mediated preconditioning of neurons against Aβ and glutamate toxicity. Similarly in vivo, pre-administration of TNF-α in mouse cortex prevented Aβ-induced apoptosis and loss of choline acetyl transferase (ChAT)-positive cholinergic neurons. However, co-administration of cbp antisense, but not scrambled oligonucleotides, negated the protective effect of TNF-α against Aβ neurotoxicity. This study illustrates a novel biological role of TNF-α in increasing neuron-specific expression of CBP for preconditioning that may have therapeutic potential against neurodegenerative disorders.

The present study examined the effects of the N-methyl-D-aspartate (NMDA) competitive antagonist, 2-amino-5-phosphonopentanoic acid (AP-5), injected into the dorsolateral striatum on the acquisition and reversal learning of a response discrimination. Male Long-Evans rats were tested across 2 consecutive days in a modified cross-maze. An infusion of either saline or AP-5 (5 or 25 nM) occurred 5 min prior to testing. In acquisition rats learned to turn left or right. In reversal learning rats learned to turn in the opposite direction. An AP-5 infusion at 25 nmol, but not 5 nmol, impaired response acquisition. Neither AP-5 dose impaired response reversal learning. The results suggest that NMDA receptors in the dorsolateral striatum are critical for the initial learning of an egocentric response discrimination.