Aberrant Presenilin-1 Expression Downregulates LDL Receptor-Related Protein (LRP): Is LRP Central to Alzheimer's Disease Pathogenesis?

A Protective Role of the Low Density Lipoprotein Receptor-related Protein against Amyloid β-Protein Toxicity

“…In addition, patients with probable AD have increased serum levels of LRP ligands including apoE, ␣ 1 -antichymotrypsin, plasmin, and urokinase (11)(12)(13), suggesting that LRP expression (or function) may be deficient in these patients. Furthermore, we have previously shown that overexpression of or mutations in the presenilin 1 (PS1) gene, which has been closely linked to the majority of early onset familial AD cases, results in significant down-regulation of LRP (5). Taken together, these data indicate that LRP plays a central role in AD pathogenesis.…”

“…Cells were maintained at 37°C (5% CO 2 atmosphere) in Dulbecco's modified Eagle's medium supplemented with 10% heat-inactivated fetal bovine serum (FBS). Human wild type and mutant PS1 (M146L) stably transfected C6 cells were also used for these experiments as described previously (5). For the surface and viability assays, cells were seeded at a density of 1 ϫ 10 5 /cm 2 .…”

“…Recent studies have suggested that altered LRP regulation may be an integral component of Alzheimer's disease (AD) pathogenesis (4,5). Importantly, LRP and its ligands, APP, apoE, and ␣ 2 m, have all been genetically linked to AD (6 -9), and colocalize in senile plaques, a hallmark of AD (4,10).…”

LRP in Alzheimer’s disease: friend or foe?

“…First, they all modulate (directly or indirectly) the metabolism of Aβ. Second, they are all linked to LRP, either as ligands (APP, apoE, α2M*) or as molecules that can affect its expression (PS1, and probably PS2) (11).…”

Transgene‐mediated RNA interference defines a novel role for notch in chemosensory startle behavior

“…While many mutations in presenilin or its homologs demonstrate gain-of-function properties with respect to increased deposition of the amyloid-␤ senile plaques (Haass and Baumeister, 1998), recent work has shown that these mutations act as partial loss-of-function with regard to Notch signaling (Song et al, 1999) and Notch function in neuronal growth in nematodes (Wittenburg et al, 2000). Some groups have begun to address the effects of presenilin loss-of-function in the fly and the mouse (Feng et al, 2001;Ye et al, 1999;Yu et al, 2001), but because of the ever-increasing number of gene products affected by presenilin (Marambaud et al, 2002;Ni et al, 2001;Van Uden et al, 1999) it is difficult to assign behavioral phenotypes to a specific pathway. Our goal is to develop a reagent that, in combination with existing resources in the Drosophila community, will enable us to selectively inhibit Notch in the adult and allow us to determine if Notch dysfunction plays a role in neurodegeneration.…”