In the past years, major efforts have been made to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been translated into extensive experimental approaches aimed at slowing down or halting disease progression. Advances in transgenic (Tg) technologies allowed the engineering of different mouse models of AD recapitulating a range of AD-like features. These Tg models provided excellent opportunities to analyze the bases for the temporal evolution of the disease. Several lines of evidence point to synaptic dysfunction as a cause of AD and that synapse loss is a pathological correlate associated with cognitive decline. Therefore, the phenotypic characterization of these animals has included electrophysiological studies to analyze hippocampal synaptic transmission and long-term potentiation, a widely recognized cellular model for learning and memory. Transgenic mice, along with non-Tg models derived mainly from exogenous application of Aβ, have also been useful experimental tools to test the various therapeutic approaches. As a result, numerous pharmacological interventions have been reported to attenuate synaptic dysfunction and improve behavior in the different AD models. To date, however, very few of these findings have resulted in target validation or successful translation into disease-modifying compounds in humans. Here, we will briefly review the synaptic alterations across the different animal models and we will recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. Finally, we will highlight intrinsic limitations in the use of experimental systems and related challenges in translating preclinical studies into human clinical trials.

Nistico', R.g., Pignatelli, M., Piccinin, S., Mercuri, N.b., Collingridge, G. (2012). Targeting synaptic dysfunction in Alzheimer's disease therapy. MOLECULAR NEUROBIOLOGY, 46(3), 572-587 [10.1007/s12035-012-8324-3].

Targeting synaptic dysfunction in Alzheimer's disease therapy

NISTICO', ROBERT GIOVANNI;MERCURI, NICOLA BIAGIO;
2012-12-01

Abstract

In the past years, major efforts have been made to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been translated into extensive experimental approaches aimed at slowing down or halting disease progression. Advances in transgenic (Tg) technologies allowed the engineering of different mouse models of AD recapitulating a range of AD-like features. These Tg models provided excellent opportunities to analyze the bases for the temporal evolution of the disease. Several lines of evidence point to synaptic dysfunction as a cause of AD and that synapse loss is a pathological correlate associated with cognitive decline. Therefore, the phenotypic characterization of these animals has included electrophysiological studies to analyze hippocampal synaptic transmission and long-term potentiation, a widely recognized cellular model for learning and memory. Transgenic mice, along with non-Tg models derived mainly from exogenous application of Aβ, have also been useful experimental tools to test the various therapeutic approaches. As a result, numerous pharmacological interventions have been reported to attenuate synaptic dysfunction and improve behavior in the different AD models. To date, however, very few of these findings have resulted in target validation or successful translation into disease-modifying compounds in humans. Here, we will briefly review the synaptic alterations across the different animal models and we will recapitulate the pharmacological strategies aimed at rescuing hippocampal plasticity phenotypes. Finally, we will highlight intrinsic limitations in the use of experimental systems and related challenges in translating preclinical studies into human clinical trials.
dic-2012
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore BIO/14 - FARMACOLOGIA
English
Con Impact Factor ISI
Animals; Synapses; Immunotherapy; Humans; Alzheimer Disease; Disease Models, Animal; Neuroprotective Agents; Signal Transduction
Nistico', R.g., Pignatelli, M., Piccinin, S., Mercuri, N.b., Collingridge, G. (2012). Targeting synaptic dysfunction in Alzheimer's disease therapy. MOLECULAR NEUROBIOLOGY, 46(3), 572-587 [10.1007/s12035-012-8324-3].
Nistico', Rg; Pignatelli, M; Piccinin, S; Mercuri, Nb; Collingridge, G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/77880
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