Persistent improvement in synaptic and cognitive functions in an Alzheimer mouse model after rolipram treatment. J Clin Invest

The Center for Dementia Research, Nathan Kline Institute for Psychiatric Research, Orangeburg, New York, USA.
Journal of Clinical Investigation (Impact Factor: 13.22). 01/2005; 114(11):1624-34. DOI: 10.1172/JCI22831
Source: PubMed

ABSTRACT Evidence suggests that Alzheimer disease (AD) begins as a disorder of synaptic function, caused in part by increased levels of amyloid beta-peptide 1-42 (Abeta42). Both synaptic and cognitive deficits are reproduced in mice double transgenic for amyloid precursor protein (AA substitution K670N,M671L) and presenilin-1 (AA substitution M146V). Here we demonstrate that brief treatment with the phosphodiesterase 4 inhibitor rolipram ameliorates deficits in both long-term potentiation (LTP) and contextual learning in the double-transgenic mice. Most importantly, this beneficial effect can be extended beyond the duration of the administration. One course of long-term systemic treatment with rolipram improves LTP and basal synaptic transmission as well as working, reference, and associative memory deficits for at least 2 months after the end of the treatment. This protective effect is possibly due to stabilization of synaptic circuitry via alterations in gene expression by activation of the cAMP-dependent protein kinase (PKA)/cAMP regulatory element-binding protein (CREB) signaling pathway that make the synapses more resistant to the insult inflicted by Abeta. Thus, agents that enhance the cAMP/PKA/CREB pathway have potential for the treatment of AD and other diseases associated with elevated Abeta42 levels.

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Available from: Ottavio V Vitolo, Feb 06, 2015
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    • "It is now widely accepted that cyclic adenosine monophosphate (cAMP) modulates synaptic plasticity and memory, and that manipulations of the cAMP/protein kinase A (PKA)/cAMP responsive element binding protein (CREB) pathway significantly affect cognitive functions. The impairment of PKA/CREB activity has been observed in the brain of AD patients and AD animal models (Gong et al., 2004; Liang et al., 2007; Yamamoto-Sasaki et al., 1999), thus leading to the hypothesis that cAMP-enhancing strategies may be beneficial for the treatment of memory loss in AD and other neurodegenerative diseases (Bruno et al., 2011, 2014; Burgin et al., 2009, Ricciarelli et al., 2015). Notably, different lines of evidence indicate that cAMP can stimulate both APP synthesis and its amyloidogenic processing (Canepa et al., 2013; Lee et al., 1997; Marambaud et al., 1998). "
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    ABSTRACT: For some decades, amyloid β (Aβ) has only been considered as a cytotoxic peptide, putative cause and marker of Alzheimer's disease (AD). Today, however, a considerable amount of evidence goes against the classical amyloid hypothesis and illustrates a new picture in which the Aβ loss of function, rather than its accumulation, has a pathogenic role in AD. In this concise review, we summarize some highlights of a collection of research pointing to the physiological function of Aβ and its role in the mechanisms of memory formation.
    Mechanisms of ageing and development 09/2015; DOI:10.1016/j.mad.2015.09.001 · 3.40 Impact Factor
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    • "associative memory deficits in a transgenic mouse model of Alzheimer's disease (Gong et al, 2004). However, non-selective PDE4 inhibitors are poorly tolerated in humans owing to nausea and emesis arising from inhibition of PDE4 in the brain stem (Mori et al, 2010) and gut (Menniti et al, 2006) at doses required for clinical effectiveness. "
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    ABSTRACT: Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4B(Y358C) mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4B(Y358C) mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4B(Y358C) mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4B(Y358C) mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4B(Y358C) mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.Neuropsychopharmacology accepted article preview online, 14 August 2015. doi:10.1038/npp.2015.240.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 08/2015; DOI:10.1038/npp.2015.240 · 7.05 Impact Factor
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    • "Conversely, basal synaptic transmission was similar in all groups analyzed. In this line, it has been described that PKA activity is not involved in the regulation of hippocampal synaptic transmission under basal conditions (Abel et al., 1997; Gong et al., 2004; Lu et al., 2008). In agreement with these observations, R6/2 mice, like R6/1, have increased PKA activity in the hippocampus (Giralt et al., 2011a) and normal basal synaptic transmission (Murphy et al., 2000). "
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    ABSTRACT: Stimulation of dopamine D1 receptor (D1R) and adenosine A2A receptor (A2AR) increases cAMP-dependent protein kinase (PKA) activity in the brain. In Huntington's disease, by essentially unknown mechanisms, PKA activity is increased in the hippocampus of mouse models and patients and contributes to hippocampal-dependent cognitive impairment in R6 mice. Here, we show for the first time that D1R and A2AR density and functional efficiency are increased in hippocampal nerve terminals from R6/1 mice, which accounts for increased cAMP levels and PKA signaling. In contrast, PKA signaling was not altered in the hippocampus of Hdh(Q7/Q111) mice, a full-length HD model. In line with these findings, chronic (but not acute) combined treatment with D1R plus A2AR antagonists (SCH23390 and SCH58261, respectively) normalizes PKA activity in the hippocampus, facilitates long-term potentiation in behaving R6/1 mice, and ameliorates cognitive dysfunction. By contrast, chronic treatment with either D1R or A2AR antagonist alone does not modify PKA activity or improve cognitive dysfunction in R6/1 mice. Hyperactivation of both D1R and A2AR occurs in HD striatum and chronic treatment with D1R plus A2AR antagonists normalizes striatal PKA activity but it does not affect motor dysfunction in R6/1 mice. In conclusion, we show that parallel alterations in dopaminergic and adenosinergic signaling in the hippocampus contribute to increase PKA activity, which in turn selectively participates in hippocampal-dependent learning and memory deficits in HD. In addition, our results point to the chronic inhibition of both D1R and A2AR as a novel therapeutic strategy to manage early cognitive impairment in this neurodegenerative disease. Copyright © 2014. Published by Elsevier Inc.
    Neurobiology of Disease 11/2014; 74C:41-57. DOI:10.1016/j.nbd.2014.11.004 · 5.08 Impact Factor
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