Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.

By C. Saura, Se-Young Choi, V. Beglopoulos, Seema Malkani, Dawei Zhang, B. Rao, Sumantra Chattarji, R. J. Kelleher, E. Kandel, K. Duff and 2 more. Neuron, 2004

748 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/5780e22fc88f69fcc0bdec534e091bc3fc8e5e75

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. Alexei Verkhratsky
2. Ilya Bezprozvanny

In Neurology

1. Alexei Verkhratsky

In Physiology

1. Richard O'Brien
2. Alexei Verkhratsky
3. P. Saftig
4. Philip C. Wong
5. Ilya Bezprozvanny
6. B. de Strooper

Citations in the corpus

• Presenilins form ER Ca2+ leak channels, a function disrupted by familial Alzheimer's disease-linked mutations. (2006, background): “The ‘‘loss of presenilin function’’ hypothesis of FAD was put forward based on the analysis of age-dependent neu- rodegeneration in PS1/2 cDKO mice (Saura et al., 2004).”
• The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex (2010, background): “Notch signals govern the decision between neuronal (in an inhibitory fashion) and glial lineages (promoting this fate), modulate the fate of terminally differentiated neurons, and affect neuronal migration and even learning and memory (Yu et al., 2001; Costa et al., 2003; Saura et al., 2004; Wang et”
• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Similarly, conditional KO of PSEN1 and PSEN2 to inhibit Aβ production also led to impaired synaptic plasticity and cognitive deficits in animal models.(393) In contrast, application of nanomolar synthetic Aβ successfully enhanced the cognitive and memory performance of the mice.”
• Amyloid Precursor Protein Processing and Alzheimer’s Disease (2011, background): “Conditional PS1 deletions result in impairments in memory and in hippocampal synaptic plasticity (Saura et al. 2004), whereas nicastrin heterozygote knockout mice develop skin tumors (Li et al. 2007b).”
• Picomolar amyloid-β positively modulates synaptic plasticity and memory in hippocampus (2008, background): “It should also be noted that our results are consistent with loss of function studies in mice lacking APP, presenilin, or BACE1 (Dawson et al., 1999; Phinney et al., 1999; Seabrook et al., 1999; Saura et al., 2004; Laird et al., 2005; Dewachter et al., 2006).”
• Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons. (2005, background): “as conditioning knockout of both PS1 and PS2 in the forebrain of adult mice causes a remarkable impairment of memory, LTP, NMDA responses, and CREB/CBP-mediated gene expression and promotes neurodegeneration (562).”
• Lysosomal Proteolysis and Autophagy Require Presenilin 1 and Are Disrupted by Alzheimer-Related PS1 Mutations (2010, neutral): “, 2002) and PS cKO mice (Saura et al., 2004) were studied at 13 month and 2–3 month, respectively, together with age-matched controls.”
• Neurotoxicity of amyloid β-protein: synaptic and network dysfunction. (2012, neutral): “1999), PS1 (Saura et al. 2004), or BACE1 (Laird et al.”
• Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. (2007, neutral): “…Pezawas et al., 2004; Qiao et al., 1998; Rattiner et al., 2004; Tokuyama et al., 2000), and they have also been implicated in brain disorders that involve cognitive decline (Howells et al., 2000; Peng et al., 2005; Phillips et al., 1991; Saura et al., 2004; Tong et al., 2004; Zuccato et al., 2001).”