Abstract
Mutations in presenilins are the major cause of familial Alzheimer's disease, but the pathogenic mechanism by which presenilin mutations cause memory loss and neurodegeneration remains unclear. Here we demonstrate that conditional double knockout mice lacking both presenilins in the postnatal forebrain exhibit impairments in hippocampal memory and synaptic plasticity. These deficits are associated with specific reductions in NMDA receptor-mediated responses and synaptic levels of NMDA receptors and alphaCaMKII. Furthermore, loss of presenilins causes reduced expression of CBP and CREB/CBP target genes, such as c-fos and BDNF. With increasing age, mutant mice develop striking neurodegeneration of the cerebral cortex and worsening impairments of memory and synaptic function. Neurodegeneration is accompanied by increased levels of the Cdk5 activator p25 and hyperphosphorylated tau. These results define essential roles and molecular targets of presenilins in synaptic plasticity, learning and memory, and neuronal survival in the adult cerebral cortex.
MeSH Terms
Activating Transcription Factor 1
Age Factors
Animals
Antibodies, Monoclonal/metabolism
Association Learning/physiology
Behavior, Animal
Blotting, Western/methods
Brain/anatomy & histology,metabolism
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Carrier Proteins/genetics,metabolism
Cyclin-Dependent Kinase 5
Cyclin-Dependent Kinases/metabolism
DNA-Binding Proteins
Disease Models, Animal
Excitatory Amino Acid Agonists/pharmacology
Fear/physiology
Gene Expression Regulation
Gene Products, gag/metabolism
Immunohistochemistry/methods
In Vitro Techniques
Lamin Type B/genetics,metabolism
Long-Term Potentiation/genetics,physiology
Membrane Potentials/physiology
Membrane Proteins/genetics,metabolism,physiology
Memory Disorders/metabolism
Mice
Mice, Knockout
Microtubule-Associated Proteins/metabolism
N-Methylaspartate/pharmacology
Neurodegenerative Diseases/metabolism
Neuronal Plasticity/physiology
Patch-Clamp Techniques
Precipitin Tests/methods
Presenilin-1
Protein Serine-Threonine Kinases/metabolism
Proto-Oncogene Proteins c-fos/genetics,metabolism
RNA, Messenger/biosynthesis
Reaction Time/genetics,physiology
Receptors, N-Methyl-D-Aspartate/drug effects,metabolism
Reverse Transcriptase Polymerase Chain Reaction/methods
Time Factors
Transcription Factors/genetics,metabolism
Viral Proteins/metabolism
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid/pharmacology
gag Gene Products, Human Immunodeficiency Virus
Chemicals
Activating Transcription Factor 1
Antibodies, Monoclonal
Atf1 protein, mouse
Carrier Proteins
DNA-Binding Proteins
Excitatory Amino Acid Agonists
Gene Products, gag
HIV gag protein p25
Lamin Type B
Membrane Proteins
Microtubule-Associated Proteins
Presenilin-1
Proto-Oncogene Proteins c-fos
RNA, Messenger
Receptors, N-Methyl-D-Aspartate
Transcription Factors
Viral Proteins
citrate-binding transport protein
gag Gene Products, Human Immunodeficiency Virus
lamin B1
tau-1 monoclonal antibody
N-Methylaspartate
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
Cyclin-Dependent Kinase 5
Protein Serine-Threonine Kinases
Calcium-Calmodulin-Dependent Protein Kinase Kinase
Cdk5 protein, mouse
Cyclin-Dependent Kinases
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
Saura Carlos A
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Choi Se-Young
Beglopoulos Vassilios
Malkani Seema
Zhang Dawei
Shankaranarayana Rao B S
Chattarji Sumantra
Kelleher Raymond J
Kandel Eric R
Duff Karen
Kirkwood Alfredo
Shen Jie
