Presenilins are essential for regulating neurotransmitter release

Zhang, Chen; Wu, Bo; Beglopoulos, Vassilios; Wines-Samuelson, Mary; Zhang, Dawei; Dragatsis, Ioannis; Südhof, Thomas C.; Shen, Jie

doi:10.1038/nature08177

Cited by 256 publications

(290 citation statements)

References 34 publications

Supporting

Mentioning

265

Contrasting

Unclassified

Order By: Relevance

“…Specifically, the presynaptic deficits, such as reduced synaptic facilitation and release probability, are first detected in PS cDKO mice at age 5 wk, followed by impairment in LTP and NMDAR-mediated responses at age 6 wk (19). Both reduced NMDAR responses and decreased neurotransmitter release probability are thought to contribute to the LTP deficits, because presynaptic inactivation of PS is sufficient to cause LTP impairment in the absence of reduction in NMDAR responses (13,23).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, γ-secretase-independent activities of PS have been suggested, including targeting the v-ATPase V0a1 subunit to lysosomes (14). We previously reported that PS is required for neurotransmitter release as well as for short-and long-term synaptic plasticity in the hippocampal Schaffer collateral pathway (9,19,23). Specifically, the presynaptic deficits, such as reduced synaptic facilitation and release probability, are first detected in PS cDKO mice at age 5 wk, followed by impairment in LTP and NMDAR-mediated responses at age 6 wk (19).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Synaptic dysfunction is widely thought to play a key role in the pathogenesis of Alzheimer's disease (AD). Presenilins, the major gene products involved in familial AD, are essential for short-and long-term synaptic plasticity in mature neurons as well as for the survival of cortical neurons during aging. Presenilin and nicastrin are both indispensable components of the γ-secretase complex, but it remains unknown whether presenilin regulates synaptic function in a γ-secretase-dependent or γ-secretase-independent manner and whether nicastrin plays similar roles in central synapses. In the current study, we address these questions using an electrophysiological approach to analyze nicastrin conditional knockout (cKO) mice in the hippocampal Schaffer collateral pathway. In these mice, we found that, even at 2 mo of age, deletion of nicastrin in excitatory neurons of the postnatal forebrain using Cre recombinase expressed under the control of the αCaMKII promoter led to deficits in presynaptic short-term plasticity including paired-pulse facilitation and frequency facilitation. Depletion of Ca 2+ in the endoplasmic reticulum mimics and occludes the presynaptic facilitation deficits in nicastrin cKO mice, suggesting that disrupted intracellular Ca 2+ homeostasis underlies the presynaptic deficits. In addition, NMDA receptor-mediated responses and long-term potentiation induced by theta-burst stimulation were decreased in nicastrin cKO mice at 3 mo but not at 2 mo of age. Together, these findings show that, similar to presenilins, nicastrin plays essential roles in the regulation of short-and longterm synaptic plasticity, highlighting the importance of γ-secretase in the function of mature synapses.A lzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The majority of familial AD cases are caused by missense mutations in genes encoding presenilin 1 (PS1) and presenilin 2, which are crucial components of the γ-secretase complex responsible for intramembrane cleavages of type I membrane proteins such as Notch. In addition to presenilin (PS), nicastrin (Nct), presenilin enhancer 2 (Pen-2), and anterior pharynx defective 1 (Aph-1) also are required to form the active γ-secretase complex. Nct is a type-1 transmembrane glycoprotein that originally was identified by its ability to form high molecular weight complexes with PS (1). Nct −/− mice die by embryonic day 10.5 and exhibit patterning defects similar to those in embryos lacking PS or Notch (2-7).In the adult brain, genetic studies using conditional genetargeting approaches demonstrated that both PS and Nct are essential for long-term memory and age-dependent neuronal survival (8-12). These findings highlight the importance of γ-secretase in memory and neuronal survival (13), even though γ-secretase-independent activities of PS have been reported also (14). However, Notch is unlikely to be the key mediator of γ-secretase in the adult brain, because Notch1 and Notch2 conditional knockout (cKO)...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synaptic function of nicastrin in hippocampal neurons

Lee

Sharma

Südhof

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…It is of particular interest that Pittsburgh Compound B, a probe for amyloid imaging by positron emission tomography, selectively binds to N3pE-Aβ 26 , implying that N3pE-Aβ42/43 could be particularly prone to seed deposition of other Aβ species, consistent with previous reports 28 . It is also possible that the mutation might affect the interaction of PS1 with other substrates or alter its property of non-γ-secretase activity 29 .…”

Section: Months Of Age (Data Not Shown) These Observations Point To mentioning

confidence: 99%

“…6f-h). Interestingly, Aβ species with the 3rd N-terminal residue converted to pyroglutamate (N3pE-Aβ), a potently pathogenic Aβ subspecies [26][27][28][29] , also colocalized with plaque cores and deposited more abundantly in APP Tg x PS1-R278I mice than in APP Tg x PS1-M146V animals ( Supplementary Fig. 14).…”

mentioning

confidence: 99%

Potent amyloidogenicity and pathogenicity of Aβ43

et al. 2011

View full text Add to dashboard Cite

Aβ42 is known to be a primary amyloidogenic and pathogenic agent in Alzheimer's disease. However, the role of Aβ43, found just as frequently in patient brains, remains unresolved. We generated knockin mice containing a pathogenic presenilin-1 R278I mutation that causes overproduction of Aβ43. Homozygous mice exhibited embryonic lethality, indicating that the mutation involves loss of function. Crossing amyloid precursor protein transgenic mice with heterozygous mutant mice resulted in elevation of Aβ43 levels, impairment of short-term memory, and acceleration of Aβ pathology, accompanying pronounced accumulation of Aβ43 in plaque cores similar to the biochemical composition observed in patient brains. Consistently, Aβ43 showed a higher propensity to aggregate and was more neurotoxic than Aȕ42. Other pathogenic presenilin mutations also caused overproduction of Aβ43 in a manner correlating with Aβ42 and with age of disease onset. These findings indicate that Aβ43, an overlooked species, is potently amyloidogenic, neurotoxic, and abundant in vivo. 3 Alzheimer's disease, the most common form of dementia, is characterized by two pathological features in the brain, extracellular senile plaques and intracellular neurofibrillary tangles. Senile plaques consist of amyloid-β peptide (Aβ) generated from amyloid precursor protein (APP) through sequential proteolytic processing by β-secretase and γ-secretase. Two major forms of Aβ exist, Aβ40 and Aβ42, with Aβ42 being more neurotoxic due to its higher hydrophobicity, which results in faster oligomerization and aggregation 1 . A number of mutations associated with early-onset familial Alzheimer's disease (FAD) have been identified in the APP, PSEN1 and PSEN2 genes, and these mutations lead to accelerated production of Aβ42 or an increase in the Aβ42/Aβ40 ratio. Together these findings indicate that Aβ42 plays an essential role in the initiation of pathogenesis. However, the possible involvement of longer Aβ species that also exist in Alzheimer's disease brains has not yet been fully investigated.Thus far, various longer Aβ species, such as Aβ43, Aβ45, Aβ48, Aβ49 and Aβ50, have been qualitatively described in Alzheimer's disease brains 2 . Similar Aβ species have also been found in transgenic mice that overexpress APP carrying FAD-linked mutations 3 . Further quantitative studies have revealed that Aβ43 is deposited more frequently than Aβ40 in both sporadic Alzheimer's disease (SAD) and FAD [4][5][6][7] .How these Aβ species with different C-terminal ends are generated from the precursor has mainly been investigated by cell biological and biochemical methods. A number of studies 8,9 demonstrated that γ/ε-cleavage by γ-secretase activity controls the fate of the C-terminal end. Aβ43, generated from Aβ49 via Aβ46, is subsequently converted to Aβ40 by γ-secretase whereas Aβ42 is independently generated from Aβ48 via Aβ45. It has also been reported that the FAD-associated I213T mutation in the PSEN1 gene increases the generation of longer Aβ species, such as Aβ43, Aβ45 a...

show abstract

“…The pathogenesis of AD begins with impaired synaptic function, which may result from the accumulation of amyloid-β (Aβ) peptide (5)(6)(7)(8). For many years, researchers have focused on the insoluble deposits of amyloid fibrils as the leading cause of memory loss and as the culprit of AD.…”

mentioning

confidence: 99%

Linking type 2 diabetes and Alzheimer's disease

Han

2010

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Presenilins are essential for regulating neurotransmitter release

Cited by 256 publications

References 34 publications

Synaptic function of nicastrin in hippocampal neurons

Synaptic function of nicastrin in hippocampal neurons

Potent amyloidogenicity and pathogenicity of Aβ43

Linking type 2 diabetes and Alzheimer's disease

Contact Info

Product

Resources

About