Claus U Pietrzik13
Sandra Baches6
Elaine Waldron3
Edward H Koo3
13Claus U Pietrzik
6Sandra Baches
3Elaine Waldron
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Increasing evidence has implicated the low density lipoprotein receptor-related protein (LRP) and the adaptor protein FE65 in Alzheimer's disease pathogenesis. We have shown previously that LRP mediates beta-amyloid precursor protein (APP) processing and affects amyloid beta-protein and APP secretion and APP-c-terminal fragment generation. Furthermore, LRP(More)
The low-density lipoprotein receptor-related protein (LRP) has recently been implicated in numerous intracellular signaling functions, as well as in Alzheimer's disease pathogenesis. Studies have shown that the beta-amyloid precursor protein (APP) interacts with LRP and that this association may impact the production of amyloid beta-protein (Abeta). In this(More)
According to the "amyloid hypothesis", the amyloid-β (Aβ) peptide is the toxic intermediate driving Alzheimer's disease (AD) pathogenesis. Recent evidence suggests that the low density lipoprotein receptor-related protein 1 (LRP1) transcytoses Aβ out of the brain across the blood-brain barrier (BBB). To provide genetic evidence for LRP1-mediated(More)
The blood-brain barrier (BBB) facilitates amyloid-β (Aβ) exchange between the blood and the brain. Here, we found that the cellular prion protein (PrP(c)), a putative receptor implicated in mediating Aβ neurotoxicity in Alzheimer's disease (AD), participates in Aβ transcytosis across the BBB. Using an in vitro BBB model, [(125)I]-Aβ(1-40) transcytosis was(More)
Alzheimer's disease (AD) is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA). Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that(More)
The low density lipoprotein receptor-related protein 1 (LRP1) emerges to play fundamental roles in cellular signaling pathways in the brain. One of its prominent ligands is the serine proteinase tissue-type plasminogen activator (tPA), which has been shown to act as a key activator of neuronal mitogen-activated protein kinase pathways via the(More)
Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive(More)
The Swedish mutation within the amyloid precursor protein (APP) causes early-onset Alzheimer's disease due to increased cleavage of APP by BACE1. While beta-secretase shedding of Swedish APP (APPswe) largely results from an activity localized in the late secretory pathway, cleavage of wild-type APP occurs mainly in endocytic compartments. However, we show(More)
We present a computational method for the reaction-based de novo design of drug-like molecules. The software DOGS (Design of Genuine Structures) features a ligand-based strategy for automated 'in silico' assembly of potentially novel bioactive compounds. The quality of the designed compounds is assessed by a graph kernel method measuring their similarity to(More)
Mutations in both the amyloid precursor protein (APP) and the presenilin (PSEN) genes cause familial Alzheimer's disease (FAD) with autosomal dominant inheritance and early onset of disease. The clinical course and neuropathology of FAD and sporadic Alzheimer's disease are highly similar, and patients with FAD constitute a unique population in which to(More)