title: Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1).
abstract: Alzheimer's disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the APP processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wild-type mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD.
authors: Department of Brain and Cognitive Sciences, Picower Institute for Learning and Memory, and Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Paola
authors: P
authors: Giusti-Rodríguez
authors: Jun
authors: J
authors: Gao
authors: Johannes
authors: J
authors: Gräff
authors: Damien
authors: D
authors: Rei
authors: Takahiro
authors: T
authors: Soda
authors: Li-Huei
authors: LH
authors: Tsai
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000172:deficiency*; D001362:Avoidance Learning / Q000502:physiology; D001703:Biophysics; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000235:genetics; D016923:Cell Death / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D046352:Freezing Reaction, Cataleptic / Q000502:physiology; D007839:Functional Laterality; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics; D006624:Hippocampus / Q000473:pathology; D066298:In Vitro Techniques; D017774:Long-Term Potentiation / Q000235:genetics; D008569:Memory Disorders / Q000209:etiology / Q000378:metabolism / Q000628:therapy; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D019636:Neurodegenerative Diseases / Q000150:complications / Q000473:pathology*; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D010770:Phosphotransferases; D016548:Prosencephalon / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D016708:Synaptophysin / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C492236:Cdk5r1 protein, mouse; D009419:Nerve Tissue Proteins; D010446:Peptide Fragments; D016708:Synaptophysin; C075222:amyloid beta-protein (1-42); D016875:tau Proteins; D049452:Green Fluorescent Proteins; D010770:Phosphotransferases; D051360:Cyclin-Dependent Kinase 5; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse