Ana García-Osta

Phenylbutyrate ameliorates cognitive deficit and reduces tau pathology in an Alzheimer's disease mouse model.

Chromatin modification through histone acetylation is a molecular pathway involved in the regulation of transcription underlying memory storage. Sodium 4-phenylbutyrate (4-PBA) is a well-known histone deacetylase inhibitor, which increases gene transcription of a number of genes, and also exerts neuroprotective effects. In this study, we report that administration of 4-PBA reversed spatial learning and memory deficits in an established mouse model of Alzheimers disease (AD) without altering β-amyloid burden. We also observed that the phosphorylated form of tau was decreased in the AD mouse brain after 4-PBA treatment, an effect probably due to an increase in the inactive form of the glycogen synthase kinase 3β (GSK3β). Interestingly, we found a dramatic decrease in brain histone acetylation in the transgenic mice that may reflect an indirect transcriptional repression underlying memory impairment. The administration of 4-PBA restored brain histone acetylation levels and, as a most likely consequence, activated the transcription of synaptic plasticity markers such as the GluR1 subunit of the AMPA receptor, PSD95, and microtubule-associated protein-2. The results suggest that 4-PBA, a drug already approved for clinical use, may provide a novel approach for the treatment of AD.

A critical role for IGF-II in memory consolidation and enhancement

We report that, in the rat, administering insulin-like growth factor II (IGF-II, also known as IGF2) significantly enhances memory retention and prevents forgetting. Inhibitory avoidance learning leads to an increase in hippocampal expression of IGF-II, which requires the transcription factor CCAAT enhancer binding protein β and is essential for memory consolidation. Furthermore, injections of recombinant IGF-II into the hippocampus after either training or memory retrieval significantly enhance memory retention and prevent forgetting. To be effective, IGF-II needs to be administered within a sensitive period of memory consolidation. IGF-II-dependent memory enhancement requires IGF-II receptors, new protein synthesis, the function of activity-regulated cytoskeletal-associated protein and glycogen-synthase kinase 3 (GSK3). Moreover, it correlates with a significant activation of synaptic GSK3β and increased expression of GluR1 (also known as GRIA1) α-amino-3-hydroxy-5-methyl-4-isoxasolepropionic acid receptor subunits. In hippocampal slices, IGF-II promotes IGF-II receptor-dependent, persistent long-term potentiation after weak synaptic stimulation. Thus, IGF-II may represent a novel target for cognitive enhancement therapies.

Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease

Alzheimers disease (AD) and ageing are associated with impaired learning and memory, and recent findings point toward modulating chromatin remodeling through histone acetylation as a promising therapeutic strategy. Here we report that systemic administration of the HDAC inhibitor 4‐phenylbutyrate (PBA) reinstated fear learning in the Tg2576 mouse model of AD. Tg2576 mice develop age‐dependent amyloid pathology and cognitive decline that closely mimics disease progression in humans. Memory reinstatement by PBA was observed independently of the disease stage: both in 6‐month‐old Tg2576 mice, at the onset of the first symptoms, but also in aged, 12‐ to 16‐month‐old mice, when amyloid plaque deposition and major synaptic loss has occurred. Reversal of learning deficits was associated to a PBA‐induced clearance of intraneuronal Aβ accumulation, which was accompanied by mitigation of endoplasmic reticulum (ER) stress, and to restoration of dendritic spine densities of hippocampal CA1 pyramidal neurons to control levels. Furthermore, the expression of plasticity‐related proteins such as the NMDA receptor subunit NR2B and the synaptic scaffold SAP102 was significantly increased by PBA. Our data suggest that the beneficial effects of PBA in memory are mediated both via its chemical chaperone‐like activity and via the transcriptional activation of a cluster of proteins required for the induction of synaptic plasticity and structural remodeling.

Rosiglitazone rescues memory impairment in Alzheimer's transgenic mice: mechanisms involving a reduced amyloid and tau pathology.

Clinical studies suggest that agonists at peroxisome proliferator-activated receptor gamma (PPARγ) may exert beneficial effects in patients with mild-to-moderate Alzheimers disease (AD), but the mechanism for the potential therapeutic interest of this class of drugs has not yet been elucidated. Here, in mice overexpressing mutant human amyloid precursor protein, we found that chronic treatment with rosiglitazone, a high-affinity agonist at PPARγ, facilitated β-amyloid peptide (Aβ) clearance. Rosiglitazone not only reduced Aβ burden in the brain but, importantly, almost completely removed the abundant amyloid plaques observed in the hippocampus and entorhinal cortex of 13-month-old transgenic mice. In the hippocampus, neuropil threads containing phosphorylated tau, probably corresponding to dystrophic neurites, were also decreased by the drug. Rosiglitazone switched on the activated microglial phenotype, promoting its phagocytic ability, reducing the expression of proinflammatory markers and inducing factors for alternative differentiation. The decreased amyloid pathology may account for the reduction of p-tau-containing neuropil threads and for the rescue of impaired recognition and spatial memory in the transgenic mice. This study provides further insights into the mechanisms for the beneficial effect of rosiglitazone in AD patients.

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

Alzheimers disease (AD) is the most common form of dementia among the elderly. In AD patients, memory loss is accompanied by the formation of beta-amyloid plaques and the appearance of tau in a pathological form. Given the lack of effective treatments for AD, the development of new management strategies for these patients is critical. The continued failure to find effective therapies using molecules aimed at addressing the anti-beta amyloid pathology has led researchers to focus on other non-amyloid-based approaches to restore memory function. Promising non-amyloid related candidate targets include phosphosdiesterases (PDEs), and indeed, Rolipram, a specific PDE4 inhibitor, was the first compound found to effectively restore cognitive deficits in animal models of AD. More recently, PDE5 inhibitors have also been shown to effectively restore memory function. Accordingly, inhibitors of other members of the PDE family may also improve memory performance in AD and non-AD animal models. Hence, in this review, we will summarize the data supporting the use of PDE inhibitors as cognitive enhancers and we will discuss the possible mechanisms of action underlying these effects. We shall also adopt a medicinal chemistry perspective that leads us to propose the most promising PDE candidates on the basis of inhibitor selectivity, brain distribution, and mechanism of action.

Sildenafil restores cognitive function without affecting β-amyloid burden in a mouse model of Alzheimer's disease.

BACKGROUND AND PURPOSE Inhibitors of phosphodiesterase 5 (PDE5) affect signalling pathways by elevating cGMP, which is a second messenger involved in processes of neuroplasticity. In the present study, the effects of the PDE5 inhibitor, sildenafil, on the pathological features of Alzheimers disease and on memory‐related behaviour were investigated.

Amyloid beta mediates memory formation

The amyloid precursor protein (APP) undergoes sequential cleavages to generate various polypeptides, including the amyloid beta (1-42) peptide (Abeta[1-42]), which is believed to play a major role in amyloid plaque formation in Alzheimers disease (AD). Here we provide evidence that, in contrast with its pathological role when accumulated, endogenous Abeta in normal hippocampi mediates learning and memory formation. Furthermore, hippocampal injection of picomolar concentrations of exogenous Abeta(1-42) enhances memory consolidation. Correlative data suggest that Abeta peptides may exert their function via nicotinic acethylcoline receptors. Hence, Abeta peptides, including Abeta(1-42), play an important physiological role in hippocampal memory formation.

BDNF mediates the neuroprotective effect of PACAP-38 on rat cortical neurons.

In primary cultures from rat cerebral cortex, pituitary adenylate cyclase-activating polypeptide (PACAP-38) exerted a protective effect on cell death induced by the excitotoxin NMDA in neuron-enriched cultures and also on apoptotic cell death induced by serum deprivation in mixed neuronal–glial cultures. The neuroprotective effect was already observed at subnanomolar concentrations of PACAP and was slightly more pronounced against excitotoxic cell death. BDNF protein expression was reduced by NMDA and much more markedly by serum deprivation (∼28 and 93% reduction respectively). In both cellular injury conditions, the diminished BDNF expression was significantly prevented by PACAP. When purified neuronal cultures were preincubated with an antiserum anti-BDNF, at a concentration without any intrinsic effect on cell viability, the neuprotective effect of PACAP was no longer observed. The results suggest that the neuroprotective effect of PACAP-38 is mediated, at least in part, by preventing the suppressed expression of a neurotrophin essential for cortical neuron survival.

MuSK Expressed in the Brain Mediates Cholinergic Responses, Synaptic Plasticity, and Memory Formation

Muscle-specific tyrosine kinase receptor (MuSK) has been believed to be mainly expressed and functional in muscle, in which it mediates the formation of neuromuscular junctions. Here we show that MuSK is expressed in the brain, particularly in neurons, as well as in non-neuronal tissues. We also provide evidence that MuSK expression in the hippocampus is required for memory consolidation, because temporally restricted knockdown after training impairs memory retention. Hippocampal disruption of MuSK also prevents the learning-dependent induction of both cAMP response element binding protein (CREB) phosphorylation and CCAAT enhancer binding protein β (C/EBPβ) expression, suggesting that the role of MuSK during memory consolidation critically involves the CREB–C/EBP pathway. Furthermore, we found that MuSK also plays an important role in mediating hippocampal oscillatory activity in the theta frequency as well as in the induction and maintenance of long-term potentiation, two synaptic responses that correlate with memory formation. We conclude that MuSK plays an important role in brain functions, including memory formation. Therefore, its expression and role are broader than what was believed previously.

Differential regulation by methylenedioxymethamphetamine of 5-hydroxytryptamine1A receptor density and mRNA expression in rat hippocampus, frontal cortex, and brainstem: the role of corticosteroids.

Abstract: The present study examined the effects of repeated administration to rats of 3,4‐methylenedioxymethamphetamine (MDMA, “Ecstasy”) on 5‐hydroxytryptamine1A (5‐HT1A) receptor density and mRNA expression in the hippocampus, frontal cortex, and brainstem. As expected, 7 days after subacute MDMA administration (20 mg/kg i.p. twice daily for 4 consecutive days) 5‐HT content was markedly reduced (−70%) in the hippocampus and the frontal cortex. 5‐HT1A receptor density was increased in the frontal cortex by 23% and decreased in the hippocampus and the brainstem by 25%. These changes correlated with an enhanced or diminished 5‐HT1A receptor mRNA expression in the three regions studied. To examine the influence of corticosteroids on these changes, adrenalectomized (ADX) rats received the same dosage regimen as above. Adrenalectomy by itself did not modify 5‐HT content in the brain regions examined and increased 5‐HT1A receptor density in the hippocampus (+20%) but produced no change in the frontal cortex and brainstem. Adrenalectomy also prevented MDMA‐induced changes in receptor number in the hippocampus and brainstem but not in the frontal cortex. Dexamethasone (1 mg/kg/day i.p.) administered for 7 consecutive days reversed the effects of adrenalectomy in the hippocampus but not in the frontal cortex. In the brainstem, MDMA no longer reduced 5‐HT1A receptor number in ADX rats, but a significant reduction was restored when ADX animals received the glucocorticoid treatment. The present data show that MDMA may affect 5‐HT1A receptors in a regionally dependent manner, notably through a drug effect on corticosterone release, which attenuates 5‐HT1A receptor gene transcription selectively in the hippocampus.