Macroautophagy is a lysosomal degradative pathway essential for neuron survival. Here, we show that macroautophagy requires the Alzheimer's disease (AD)-related protein presenilin-1 (PS1). In PS1 null blastocysts, neurons from mice hypomorphic for PS1 or conditionally depleted of PS1, substrate proteolysis and autophagosome clearance during macroautophagy are prevented as a result of a selectiv...

UNLABELLED Aerobic glycolysis and lactate production in the brain plays a key role in memory, yet the role of this metabolism in the cognitive decline associated with Alzheimer's disease (AD) remains poorly understood. Here we examined the relationship between cerebral lactate levels and memory performance in an APP/PS1 mouse model of AD, which progressively accumulates amyloid-β. In vivo (1)H-...

In Alzheimer disease (AD) patients, early memory dysfunction is associated with glucose hypometabolism and neuronal loss in the hippocampus. Double transgenic (Tg) mice co-expressing the M146L presenilin 1 (PS1) and K670N/M671L, the double "Swedish" amyloid precursor protein (APP) mutations, are a model of AD amyloid-beta deposition (Abeta) that exhibits earlier and more profound impairments of...

OBJECTIVE To disclose a novel mutation of the presenilin 1 (PS1) gene responsible for early-onset Alzheimer disease and to clarify genotype-phenotype correlation that should help to establish the function of this protein. BACKGROUND The PS1 and presenilin 2 (PS2) genes carry missense mutations in families with Alzheimer disease. The PS1 and PS2 proteins have similar structures, and all presen...

Aberrant regulation of glycogen synthase kinase-3 (GSK-3) is implicated in Alzheimer's disease (AD), but the mechanisms involved remain elusive. Our recent study shows that GSK-3 impairs lysosomal acidification and that inhibition of GSK-3 re-acidified lysosomes in brains of AD mice. This effect was accompanied by reductions in β-amyloid pathology and amelioration of cognitive deficits. Preseni...

Presenilin-1 null mutation (PS1 -/-) in mice is associated with morphological alterations and defects in cleavage of transmembrane proteins. Here, we demonstrate that PS1 deficiency also leads to the formation of degradative vacuoles and to the aberrant translocation of presynaptic alpha- and beta-synuclein proteins to these organelles in the perikarya of primary neurons, concomitant with signi...

The Alzheimer's disease-associated presenilin (PS) 1 is intimately involved in gamma-secretase cleavage of beta-amyloid precursor protein and other proteins. In addition, PS1 plays a role in beta-catenin signaling and in the regulation of apoptosis. Here we demonstrate that phosphorylation of PS1 is regulated by two independent signaling pathways involving protein kinase (PK) A and PKC and that...

We studied a novel function of the presenilins (PS1 and PS2) in governing capacitative calcium entry (CCE), a refilling mechanism for depleted intracellular calcium stores. Abrogation of functional PS1, by either knocking out PS1 or expressing inactive PS1, markedly potentiated CCE, suggesting a role for PS1 in the modulation of CCE. In contrast, familial Alzheimer's disease (FAD)-linked mutant...

Presenilin (PS) proteins control the proteolytic cleavage that precedes nuclear access of the Notch intracellular domain. Here we observe that a partial activation of the HES1 promoter can be detected in PS1/PS2 (PS1/2) double null cells using Notch1 Delta E constructs or following Delta 1 stimulation, despite an apparent abolition of the production and nuclear accumulation of the Notch intrace...

BACKGROUND Several lines of evidence suggest that most of the early-onset forms of familial Alzheimer's disease (FAD) are due to inherited mutations borne by a chromosome 14-encoded protein, presenilin 1 (PS1). This is likely related to an increased production of amyloid beta-peptide (A beta) 42, one of the main components of the extracellular deposits called senile plaques that invade human co...