Clearance mechanisms of Alzheimer's amyloid-β peptide: implications for therapeutic design and diagnostic tests

Abstract

Currently, the 'amyloid hypothesis' is the most widely accepted explanation for the pathogenesis of Alzheimer's disease (AD). According to this hypothesis, altered metabolism of the amyloid-b (Ab) peptide is central to the pathological cascade involved in the pathogenesis of AD. Although Ab is produced by almost every cell in the body, a physiological function for the peptide has not been determined, and the pathways by which Ab leads to cognitive dysfunction and cell death are unclear. Numerous therapeutic approaches that target the production, toxicity and removal of Ab are being developed worldwide. Although therapeutic treatment for AD may be imminent, the value and effectiveness of such treatment are largely dependent on early diagnosis of the disease. This review summarizes current knowledge of Ab clearance, transport and degradation, and evaluates the use of such information in the development of diagnostic tools. The conflicting results of plasma Ab ELISAs are discussed, as are the more promising results of Ab imaging by positron emission tomography. Current knowledge of Ab-binding proteins and Ab-degrading enzymes is analysed in the context of a potential therapy for AD. Transport across the blood-brain barrier by the receptor for advanced glycation end products and efflux via the multi-ligand lipoprotein receptor LRP-1 is also reviewed. Enhancing clearance and degradation of Ab remains an attractive therapeutic strategy, and improved understanding of Ab clearance may lead to advances in diagnostics and interventions designed to prevent or delay the onset of AD.

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

“…Electrophoresed proteins were transferred to polyvinylidene difluoride membranes (Bio-Rad) that were blocked in blocking buffer (1% (w/v) nonfat dry milk in TBS containing 0.1% (v/v) Tween 20) for 1 h at ambient temperature. Membranes were then hybridized for 1 h at ambient temperature with primary antibodies as follows: a carboxyl-terminal APP polyclonal antibody (1:400, IBL); a carboxyl-terminal PS1 monoclonal antibody (PS1-loop; 1:500, Merck Millipore); a carboxyl-terminal BACE1 polyclonal antibody (1:400, IBL); a carboxyl-terminal BACE monoclonal antibody (61-3E7, 1:1,000, Merck Millipore); an amino-terminal A␤ 1-16 monoclonal antibody (82E1; 1:150, IBL), an amino-terminal A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17] monoclonal antibody (6E10; 1:1,000, Merck Millipore); a nicastrin polyclonal antibody (corresponds to amino acid residues 688 -708 from human nicastrin) (1:1000, Thermo Fisher Scientific, Waltham, MA); an amino-terminal presenilin enhancer 2 (PEN-2) polyclonal antibody (1:250, Thermo Fisher Scientific); an actin polyclonal antibody (1:500, Santa Cruz Biotechnology, Santa Cruz, CA) as a loading control, or a ␤-actin monoclonal antibody (AC-74, 1:4,000, Sigma) as a loading control. Membranes were then rinsed three times for 30 min each in TBS containing 0.1% (v/v) Tween 20 and incubated for 1 h at ambient temperature with appropriate horseradish peroxidase-conjugated secondary antibodies.…”

“…Based on the "amyloid cascade hypothesis" of AD, which theorizes that cerebral A␤ accumulation sets a toxic downstream cascade into motion (2,4,5), a surge of research activity has been directed toward anti-amyloid therapeutics. Specific approaches have included the following: preventing the self-assembly of A␤ into soluble oligomers and insoluble deposits, enhancing A␤ degradation, directly or indirectly targeting A␤ neurotoxicity, preventing or reducing A␤ production, and improving A␤ efflux from the brain into the peripheral blood (6).…”

Multiple Low-Dose Infusions of Human Umbilical Cord Blood Cells Improve Cognitive Impairments and Reduce Amyloid-β-Associated Neuropathology in Alzheimer Mice

“…Most interventions address one or more of the following therapeutic approaches: preventing oligomerization of Ab and deposition, enhancing Ab degradation, targeting Ab neurotoxicity directly or indirectly, preventing or reducing Ab production, and improving Ab efflux from the brain into the peripheral blood plasma [43]. We chose to administer multiple low doses of HUCBCs based on our optimized method for reduction of vascular and parenchymal deposits used previously [24].…”

ATP-binding Cassette Transporter A1 Mediates the Beneficial Effects of the Liver X Receptor Agonist GW3965 on Object Recognition Memory and Amyloid Burden in Amyloid Precursor Protein/Presenilin 1 Mice*

“…The cause of AD in more than 95% of subjects that typically develop AD in late life is unknown. As production of A␤ is generally not altered in these patients, age-related defects in A␤ degradation and clearance is emerging as a leading hypothesis for development of AD in the majority of patients (5).…”