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The β-Secretase Enzyme BACE in Health and Alzheimer's Disease: Regulation, Cell Biology, Function, and Therapeutic Potential
This review summarizes BACE properties, describes BACE translation dysregulation in AD, and discusses BACE physiological functions in sodium current, synaptic transmission, myelination, and schizophrenia.
Alzheimer's disease: the cholesterol connection
The identification of a variant of the apolipoprotein E (APOE) gene as a major genetic risk factor for AD is also consistent with a role for cholesterol in the pathogenesis of AD.
BACE1 regulates voltage-gated sodium channels and neuronal activity
BACE1 inhibitors may normalize membrane excitability in Alzheimer's disease patients with elevated BACE1 activity and regulate Nav1 α-subunit levels and controls cell-surface sodium current densities.
A three-dimensional human neural cell culture model of Alzheimer’s disease
This work reports that FAD mutations in β-amyloid precursor protein and presenilin 1 are able to induce robust extracellular deposition of amyloid-β, including amyloids-β plaques, in a human neural stem-cell-derived three-dimensional (3D) culture system, and successfully recapitulated Alzheimer’s disease pathology in a single 3D human neural cell culture system.
The many substrates of presenilin/γ-secretase.
The current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex is reviewed to recapitulate the current knowledge on the possible physiological function of PS/ γ- secretase-mediated cleavage of specific substrate proteins.
Alzheimer–associated presenilins 1 and 2 : Neuronal expression in brain and localization to intracellular membranes in mammalian cells
Using in situ hybridization, it is demonstrated that the expression patterns of PS1 and PS2 in the brain are extremely similar to each other and that messages for both are primarily detectable in neuronal populations.
Ceramide stabilizes beta-site amyloid precursor protein-cleaving enzyme 1 and promotes amyloid beta-peptide biogenesis.
- L. Puglielli, Blake C. Ellis, A. Saunders, D. Kovacs
- Biology, ChemistryThe Journal of biological chemistry
Data indicate that the lipid second messenger ceramide, which is elevated in the brains of Alzheimer's disease patients, increases the half-life of BACE1 and thereby promotes Abeta biogenesis.
Acyl-coenzyme A: cholesterol acyltransferase modulates the generation of the amyloid β-peptide
It is found that cholesteryl-ester levels are directly correlated with Aβ production, and pharmacological inhibitors of ACAT, developed for the treatment of atherosclerosis, are potent modulators of Aβ generation, indicating their potential for use in thereatment of Alzheimer's disease.
The gene defects responsible for familial Alzheimer's disease.
While the exact mechanisms by which the known FAD gene changes lead to the onset of AD remain unclear, the available data indicate that novel therapies aimed at curbing the generation, aggregation, and deposition of A beta would appear to carry the greatest potential for the effective treatment of this formidable disease.