Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.
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.
Saura
Carlos A
CA
Center for Neurologic Diseases, Brigham and Women's Hospital, Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Choi
Se-Young
SY
Beglopoulos
Vassilios
V
Malkani
Seema
S
Zhang
Dawei
D
Shankaranarayana Rao
B S
BS
Chattarji
Sumantra
S
Kelleher
Raymond J
RJ
Kandel
Eric R
ER
Duff
Karen
K
Kirkwood
Alfredo
A
Shen
Jie
J
D051697:Activating Transcription Factor 1; D000367:Age Factors; D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D001245:Association Learning / Q000502:physiology; D001522:Behavior, Animal; D015153:Blotting, Western / Q000379:methods; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004268:DNA-Binding Proteins; D004195:Disease Models, Animal; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005239:Fear / Q000502:physiology; D005786:Gene Expression Regulation; D015683:Gene Products, gag / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D034921:Lamin Type B / Q000235:genetics / Q000378:metabolism; D017774:Long-Term Potentiation / Q000235:genetics / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008569:Memory Disorders / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D016202:N-Methylaspartate / Q000494:pharmacology; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D018408:Patch-Clamp Techniques; D011233:Precipitin Tests / Q000379:methods; D053764:Presenilin-1; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011930:Reaction Time / Q000235:genetics / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000494:pharmacology; D054301:gag Gene Products, Human Immunodeficiency Virus
D051697:Activating Transcription Factor 1; D000911:Antibodies, Monoclonal; C497100:Atf1 protein, mouse; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D018690:Excitatory Amino Acid Agonists; D015683:Gene Products, gag; C059827:HIV gag protein p25; D034921:Lamin Type B; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D053764:Presenilin-1; D016760:Proto-Oncogene Proteins c-fos; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D014764:Viral Proteins; C020723:citrate-binding transport protein; D054301:gag Gene Products, Human Immunodeficiency Virus; C085348:tau-1 monoclonal antibody; D016202:N-Methylaspartate; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; C495906:Cdk5 protein, mouse; D018844:Cyclin-Dependent Kinases