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.

• Publication year

  2004

• Venue

  Neuron

• Publication date

  2004-04-08

• Fields of study

  Biology, Medicine, Psychology

• Identifiers
  DOI 10.1016/S0896-6273(04)00182-5PMID 15066262
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations.

  2003cited by this paper
• Alzheimer-associated C allele of the promoter polymorphism -22C>T causes a critical neuron-specific decrease of presenilin 1 expression.

  2003cited by this paper
• A presenilin dimer at the core of the γ-secretase enzyme: Insights from parallel analysis of Notch 1 and APP proteolysis

  2003influential reference
• Presenilin 1 is involved in maturation and trafficking of N‐cadherin to the plasma membrane

  2003cited by this paper
• APP processing and synaptic function.

  2003cited by this paper
• Impaired Long-Term Memory and NR2A-Type NMDA Receptor-Dependent Synaptic Plasticity in Mice Lacking c-Fos in the CNS

  2003cited by this paper
• The molecular basis of CaMKII function in synaptic and behavioural memory

  2002cited by this paper
• Chronic Stress Induces Contrasting Patterns of Dendritic Remodeling in Hippocampal and Amygdaloid Neurons

  2002cited by this paper
• Amyloid β-peptide inhibition of the PKA/CREB pathway and long-term potentiation: Reversibility by drugs that enhance cAMP signaling

  2002cited by this paper
• Function and regulation of CREB family transcription factors in the nervous system.

  2002cited by this paper
• Disruption of Dendritic Translation of CaMKII Impairs Stabilization of Synaptic Plasticity and Memory

  2002cited by this paper
• Disruption of CREB function in brain leads to neurodegeneration

  2002cited by this paper
• Presenilin-1 mutations of leucine 166 equally affect the generation of the Notch and APP intracellular domains independent of their effect on Aβ42 production

  2002influential reference
• alpha- and betaCaMKII. Inverse regulation by neuronal activity and opposing effects on synaptic strength.

  2002cited by this paper
• A presenilin 1 mutation associated with familial frontotemporal dementia inhibits gamma-secretase cleavage of APP and notch.

  2002cited by this paper
• Disruption of dendritic translation of CaMKIIα impairs stabilization of synaptic plasticity and memory consolidation

  2002cited by this paper
• Disruption of dendritic translation of CaMKIIalpha impairs stabilization of synaptic plasticity and memory consolidation.

  2002cited by this paper
• Reduced Expression of Amyloid Precursor Protein, Presenilin-1 and rab3a in Cortical Brain Regions in Alzheimer’s Disease

  2001cited by this paper
• The Molecular Biology of Memory Storage: A Dialogue Between Genes and Synapses

  2001influential reference
• APP processing and synaptic plasticity in presenilin-1 conditional knockout mice.

  2001influential reference
• Protein synthesis at synaptic sites on dendrites.

  2001cited by this paper
• β-Amyloid-(1–42) Impairs Activity-dependent cAMP-response Element-binding Protein Signaling in Neurons at Concentrations in Which Cell Survival Is Not Compromised*

  2001cited by this paper
• A transcriptionally [correction of transcriptively] active complex of APP with Fe65 and histone acetyltransferase Tip60.

  2001cited by this paper
• Activated cAMP-response Element-binding Protein Regulates Neuronal Expression of Presenilin-1*

  2001cited by this paper
• Interference by Huntingtin and Atrophin-1 with CBP-Mediated Transcription Leading to Cellular Toxicity

  2001cited by this paper
• A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60

  2001cited by this paper
• The Presenilin 1 C92S Mutation Increases Aβ 42 Production

  2000cited by this paper
• NMDA receptor-mediated control of protein synthesis at developing synapses

  2000influential reference
• Presenilin-1 regulates neuronal differentiation during neurogenesis.

  2000cited by this paper
• Is CREB a key to neuronal survival?

  2000cited by this paper
• The presenilin 1 C92S mutation increases abeta 42 production.

  2000cited by this paper
• Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.

  1999cited by this paper
• Mice lacking both presenilin genes exhibit early embryonic patterning defects.

  1999influential reference
• A Loss of Function Mutation of Presenilin-2 Interferes with Amyloid β-Peptide Production and Notch Signaling*

  1999cited by this paper
• Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration

  1999influential reference
• Proteolytic release and nuclear translocation of Notch-1 are induced by presenilin-1 and impaired by pathogenic presenilin-1 mutations.

  1999cited by this paper
• A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain

  1999cited by this paper
• Effects of PS1 deficiency on membrane protein trafficking in neurons.

  1998cited by this paper
• A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1

  1998cited by this paper
• A presenilin-1 truncating mutation is present in two cases with autopsy-confirmed early-onset Alzheimer disease.

  1998cited by this paper
• CREB and memory.

  1998cited by this paper
• Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein

  1998cited by this paper
• Alzheimer’s disease: transiently developing dendritic changes in pyramidal cells of sector CA1 of the Ammon’s horn

  1997cited by this paper
• APPSW Transgenic Mice Develop Age‐related Aβ Deposits and Neuropil Abnormalities, but no Neuronal Loss in CA1

  1997cited by this paper
• Human presenilin-1, but not familial Alzheimer's disease (FAD) mutants, facilitate Caenorhabditis elegans Notch signalling independently of proteolytic processing.

  1997cited by this paper
• The presenilins and Alzheimer's disease.

  1997cited by this paper
• Skeletal and CNS defects in Presenilin-1-deficient mice.

  1997cited by this paper
• Presenilins and Alzheimer's disease.

  1997cited by this paper
• NMDA receptor-dependent and -independent long-term depression in the CA1 region of the adult rat hippocampus in vitro.

  1997cited by this paper
• Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice.

  1996cited by this paper
• Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice

  1996cited by this paper
• The essential role of hippocampal CA1 NMDA receptor-dependent synaptic plasticity in spatial memory.

  1996cited by this paper
• Assessment of normal and mutant human presenilin function in Caenorhabditis elegans.

  1996influential reference
• Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor.

  1995cited by this paper
• A synaptic model of memory: long-term potentiation in the hippocampus

  1993influential reference
• Physical basis of cognitive alterations in alzheimer's disease: Synapse loss is the major correlate of cognitive impairment

  1991cited by this paper
• Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease.

  1989cited by this paper
• Molecular Basis

  year unknowncited by this paper

• Modulating Cognition-Linked Histone Acetyltransferases (HATs) as a Therapeutic Strategy for Neurodegenerative Diseases: Recent Advances and Future Trends

  2025cites this paper
• Pathway-based network medicine identifies novel natural products for Alzheimer’s disease

  2025cites this paper
• Kv1.1 channel dysfunction in parvalbumin-positive interneurons contributes to anxiety-like behaviors in young adult presenilin 1/2 conditional double knockout mice

  2025influential citation
• Integration of phytochemical profiling and computational approaches to evaluate the neuroprotective potential of Nardostachys jatamansi in Alzheimer's disease

  2025cites this paper
• Identification of presenilin mutations that have sufficient gamma-secretase proteolytic activity to mediate Notch signaling but disrupt organelle and neuronal health

  2025cites this paper
• Unscrambling the cellular and molecular threads of Neuroplasticity: Insights into Alzheimer's disease pathogenesis.

  2025cites this paper
• Age- and Genotype-Dependent Effects of Chronic Nicotine on Presenilin1/2 Double Knockout Mice: From Behavior to Molecular Pathways.

  2025cites this paper
• Impaired synaptic plasticity in behaving mice by inactivation of presenilin and accumulation of the neurexin gamma-secretase proteolytic substrate.

  2025influential citation
• Presenilin Loss Impairs Synaptic Transmission and Causes Axonal Degeneration through Ryanodine Receptor Dysfunction, Independent of γ-Secretase Activity

  2025cites this paper
• Presenilin mutations disrupt iron homeostasis to promote ferroptosis mediated neurodegeneration in Caenorhabditis elegans

  2025cites this paper
• Beyond mTOR: Unraveling the Complex Pathophysiology and Signaling Pathways in Focal Cortical Dysplasia

  2025cites this paper
• Pathophysiologic abnormalities in transgenic mice carrying the Alzheimer disease PSEN1 Δ440 mutation.

  2024cites this paper
• Cortical neurodegeneration caused by Psen1 mutations is independent of Aβ

  2024influential citation
• Haploinsufficiency and Alzheimer’s Disease: The Possible Pathogenic and Protective Genetic Factors

  2024cites this paper
• Differential expression and modulation of presenilin-1 and presenilin-2 in neural cell lines

  2024cites this paper
• Modeling of age-related neurological disease: utility of zebrafish

  2024cites this paper
• Caloric Restriction Improves Spatial Learning Deficits in Tau Mice

  2024cites this paper
• Unlocking the epigenetic symphony: histone acetylation's impact on neurobehavioral change in neurodegenerative disorders.

  2024cites this paper
• In Silico Analysis of Glutamate Receptors in Capsicum chinense: Structure, Evolution, and Molecular Interactions

  2024cites this paper
• Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

  2024cites this paper
• Recording γ-secretase activity in living mouse brains

  2024cites this paper
• Mitochondrial Quality Control in Alzheimer’s Disease: Insights from Caenorhabditis elegans Models

  2024cites this paper
• Presenilin Deficiency Results in Cellular Cholesterol Accumulation by Impairment of Protein Glycosylation and NPC1 Function

  2024cites this paper
• Recording γ-secretase activity in living mouse brains

  2024cites this paper
• Altered expression of Presenilin2 impacts endolysosomal homeostasis and synapse function in Alzheimer’s disease-relevant brain circuits

  2024cites this paper
• Presenilin: A Multi-Functional Molecule in the Pathogenesis of Alzheimer’s Disease and Other Neurodegenerative Diseases

  2024cites this paper
• Presenilin-1 in smooth muscle cells facilitates hypermuscularization in elastin aortopathy

  2023cites this paper
• Presenilin-dependent regulation of tau pathology via the autophagy/proteasome pathway

  2023cites this paper
• A familial Alzheimer’s disease associated mutation in presenilin-1 mediates amyloid-beta independent cell specific neurodegeneration

  2023cites this paper
• Timp1 Deletion Induces Anxiety-like Behavior in Mice

  2023influential citation
• Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.

  2023cites this paper
• Effects of presenilin-1 familial Alzheimer’s disease mutations on γ-secretase activation for cleavage of amyloid precursor protein

  2023cites this paper
• Alzheimer’s disease linked Aβ42 exerts product feedback inhibition on γ-secretase impairing downstream cell signaling

  2023cites this paper
• Guizhi Fuling capsule relieves memory deficits by inhibition of microglial neuroinflammation through blocking JAK2/STAT3 pathway in presenilin1/2 conditional double knockout mice

  2023cites this paper
• Pathogenic Aβ production by heterozygous PSEN1 mutations is intrinsic to the mutant protein and not mediated by conformational hindrance of wild-type PSEN1

  2023cites this paper
• Neuroepigenetics of ageing and neurodegeneration-associated dementia: An updated review.

  2023cites this paper
• Cystatins: unravelling the biological implications for neuroprotection

  2023cites this paper
• Loss of presenilin-1 in smooth muscle cells ameliorates elastin aortopathy

  2023cites this paper
• Gamma secretase activity modulates BMP-7-induced dendritic growth in primary rat sympathetic neurons.

  2023cites this paper
• The amyloid cascade hypothesis: an updated critical review.

  2023cites this paper
• Glycogen synthase kinase 3β (GSK3β) and presenilin (PS) are key regulators of kinesin-1-mediated cargo motility within axons

  2023cites this paper
• Circadian rhythm sleep disorders and time-of-day-dependent memory deficiency in Presenilin1/2 conditional knockout mice with long noncoding RNA expression profiling changes.

  2023cites this paper
• Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease

  2023cites this paper
• Animal models of Alzheimer’s disease: preclinical insights and challenges

  2023cites this paper
• Analysis of Non-Amyloidogenic Mutations in APP Supports Loss of Function Hypothesis of Alzheimer’s Disease

  2023cites this paper
• Effects of electroacupuncture on urinary metabolome and microbiota in presenilin1/2 conditional double knockout mice

  2023cites this paper
• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future

  2023cites this paper
• Human Presenilin-1 delivered by AAV9 rescues impaired γ-secretase activity, memory deficits, and neurodegeneration in Psen mutant mice

  2023cites this paper
• Presenilins regulate synaptic plasticity in the perforant pathways of the hippocampus

  2023cites this paper
• Covalent fragment inhibits intramembrane proteolysis

  2022cites this paper
• Spatiotemporal patterns of gliosis and neuroinflammation in presenilin 1/2 conditional double knockout mice

  2022influential citation
• Brain transplantation of genetically corrected Sanfilippo type B neural stem cells induces partial cross-correction of the disease

  2022cites this paper
• The role of histone modifications: from neurodevelopment to neurodiseases

  2022cites this paper
• Application of Small Molecules in the Central Nervous System Direct Neuronal Reprogramming

  2022cites this paper
• Genetic inhibition of PDK1 robustly reduces plaque deposition and ameliorates gliosis in the 5×FAD mouse model of Alzheimer's disease

  2022cites this paper
• Genetics, Functions, and Clinical Impact of Presenilin-1 (PSEN1) Gene

  2022cites this paper
• Turning the tide on Alzheimer’s disease: modulation of γ-secretase

  2022cites this paper
• Title Page Title: Chronic Seizures Induce Sex-Specific Cognitive Deficits with Loss of Presenilin 2 Function Abbreviated title: Impact of Chronic Seizures with PSEN2 Knockout Authors:

  2022cites this paper
• Selective ferroptosis vulnerability due to familial Alzheimer’s disease presenilin mutations

  2022cites this paper
• Clinical and Molecular Findings in a Turkish Family Who Had a (c.879-1G>A) Splicing Variant in PSEN1 Gene with A Rare Condition: The Variant Alzheimer's Disease with Spastic Paraparesis.

  2022cites this paper
• Pterostilbene Promotes Mean Lifespan in Both Male and Female Drosophila Melanogaster Modulating Different Proteins in the Two Sexes

  2022cites this paper
• Exogenous Aβ1-42 monomers improve synaptic and cognitive function in Alzheimer's disease model mice.

  2022cites this paper
• The three sisters of fate: Genetics, pathophysiology and outcomes of animal models of neurodegenerative diseases.

  2022cites this paper
• Physiological Roles of Monomeric Amyloid-β and Implications for Alzheimer’s Disease Therapeutics

  2022cites this paper
• A novel Lgi1 mutation causes white matter abnormalities and impairs motor coordination in mice

  2022cites this paper
• The Binding of Different Substrate Molecules at the Docking Site and the Active Site of γ-Secretase Can Trigger Toxic Events in Sporadic and Familial Alzheimer’s Disease

  2022cites this paper
• Presenilin Deficiency Increases Susceptibility to Oxidative Damage in Fibroblasts

  2022cites this paper
• Flavonoids with Potential Anti-Amyloidogenic Effects as Therapeutic Drugs for Treating Alzheimer’s Disease

  2021cites this paper
• Loss of presenilin function enhances tau phosphorylation and aggregation in mice

  2021cites this paper
• Protocols for assessing neurodegenerative phenotypes in Alzheimer’s mouse models

  2021cites this paper
• Urinary metabolomic changes and microbiotic alterations in presenilin1/2 conditional double knockout mice

  2021cites this paper
• Selective expression of the neurexin substrate for presenilin in the adult forebrain causes deficits in associative memory and presynaptic plasticity.

  2021cites this paper
• Targeting Common Signaling Pathways for the Treatment of Stroke and Alzheimer’s: a Comprehensive Review

  2021cites this paper
• Analysis of Age-Dependent Alterations in Excitability Properties of CA1 Pyramidal Neurons in an APPPS1 Model of Alzheimer’s Disease

  2021cites this paper
• Peony seed oil ameliorates neuroinflammation‐mediated cognitive deficits by suppressing microglial activation through inhibition of NF‐κB pathway in presenilin 1/2 conditional double knockout mice

  2021cites this paper
• Non-productive angiogenesis disassembles Aß plaque-associated blood vessels

  2021cites this paper
• Presenilin mutations and their impact on neuronal differentiation in Alzheimer’s disease

  2021cites this paper
• Is γ-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?

  2021cites this paper
• Modification of Glial Cell Activation through Dendritic Cell Vaccination: Promises for Treatment of Neurodegenerative Diseases

  2021cites this paper
• Insight into the genetic etiology of Alzheimer's disease: A comprehensive review of the role of rare variants

  2021cites this paper
• Flexible and Accurate Substrate Processing with Distinct Presenilin/γ-Secretases in Human Cortical Neurons

  2021cites this paper
• Alzheimer’s disease-associated TM2D genes regulate Notch signaling and neuronal function in Drosophila

  2021cites this paper
• Electroacupuncture Ameliorates Neuroinflammation-Mediated Cognitive Deficits through Inhibition of NLRP3 in Presenilin1/2 Conditional Double Knockout Mice

  2021cites this paper
• Familial Alzheimer’s Disease Mutations in PSEN1 Lead to Premature Human Stem Cell Neurogenesis

  2021cites this paper
• Title Page Title: Chronic Seizures Worsen Cognitive Function with Loss of Presenilin 2 Function in a Sex-Related Manner Abbreviated title: Impact of Chronic Seizures with PSEN2 Knockout Authors:

  2021cites this paper
• A Developmental Role for Microglial Presenilin 1 in Memory

  2021cites this paper
• Pen-2 Negatively Regulates the Differentiation of Oligodendrocyte Precursor Cells into Astrocytes in the Central Nervous System

  2021cites this paper
• An insight into Alzheimer’s disease and its on-setting novel genes

  2021cites this paper
• Amyloidogenic and anti-amyloidogenic properties of presenilin 1.

  2021cites this paper
• Noncognitive species-typical and home-cage behavioral alterations in conditional presenilin 1/presenilin 2 double knockout mice.

  2021cites this paper
• TM2D genes regulate Notch signaling and neuronal function in Drosophila

  2021cites this paper
• Inactivation of Presenilin in inhibitory neurons results in decreased GABAergic responses and enhanced synaptic plasticity

  2021cites this paper
• MAM and C99, key players in the pathogenesis of Alzheimer's disease.

  2020cites this paper
• Targeting Amyloidogenic Processing of APP in Alzheimer’s Disease

  2020cites this paper
• Super-resolution microscopy reveals majorly mono- and dimeric presenilin1/γ-secretase at the cell surface

  2020cites this paper
• Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial Phenotypes

  2020cites this paper
• Post-Developmental Roles of Notch Signaling in the Nervous System

  2020cites this paper
• Visualization of PS/γ-Secretase Activity in Living Cells

  2020cites this paper
• Susceptibility to cellular stress in PS1 mutant N2a cells is associated with mitochondrial defects and altered calcium homeostasis

  2020cites this paper
• Mechanisms of neurodegeneration - Insights from familial Alzheimer's disease.

  2020cites this paper