Phenylbutyrate rescues dendritic spine loss associated with memory deficits in a mouse model of Alzheimer disease.
Alzheimer's 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.
Neuropharmacology and Behaviour, Neuroscience Department, Centro de Investigación Médica Aplicada (CIMA) y Universidad de Navarra, 31008 Pamplona, Spain.
Ana
A
Ricobaraza
Mar
M
Cuadrado-Tejedor
Sonia
S
Marco
Isabel
I
Pérez-Otaño
Ana
A
García-Osta
D000367:Age Factors; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000523:psychology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology; D049229:Dendritic Spines / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005239:Fear / Q000187:drug effects; D051528:Guanylate Kinases / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000188:drug therapy* / Q000523:psychology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010654:Phenylbutyrates / Q000008:administration & dosage*; D058225:Plaque, Amyloid / Q000188:drug therapy; D017966:Pyramidal Cells / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects
D016229:Amyloid beta-Peptides; D056572:Histone Deacetylase Inhibitors; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D010654:Phenylbutyrates; D016194:Receptors, N-Methyl-D-Aspartate; C075773:4-phenylbutyric acid; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases