45,46 Antibody binding to β-amyloid in the brain may also activate the microglial (and possibly astrocytic) mechanisms
that can reduce amyloid deposition.44,47 Critical in this formulation is the penetration of antibody into the brain. A second proposed mechanism is what has been called the “peripheral sink hypothesis.” In this case, antibody binding to β-amyloid in the blood is thought to result in a sharp concentration gradient between the blood and the brain, Inhibitors,research,lifescience,medical such that β-amyloid movement from brain to blood is accelerated, and β-amyloid concentrations drop sharply and thus reduce the rate of deposition.48 Although this mechanism initially seems highly unlikely, there is evidence for transport of β-amyloid from brain to blood, at least under some circumstances.49 Perhaps it is unnecessary for the antibody to reach the brain at all. The first clinical Inhibitors,research,lifescience,medical trials of “passive immunization” as a treatment for Alzheimer’s disease appear to be underway, and preliminary results were reported in mid-2008. In passive immunization of transgenic mice, at least Inhibitors,research,lifescience,medical some antibodies appear to cause a shift in the localization of β-amyloid from deposits in the tissue to deposition in vessel walls, with some microhemorrhages
reported.43 Human trials reported some vasculitis as a side effect in groups receiving the highest doses of antibody, although effects on rates of cognitive decline did not appear to be large, if measurable at all. Further trials of passive immunization are underway, in some cases using intravenous immunoglobulin G (IgG) fractions, with the presumption that natural IgG fractions – prepared by isolation of IgG from many thousands of donors – contain sufficient concentrations Inhibitors,research,lifescience,medical of anti-β-amyloid antibodies to reduce amyloid deposition.50,51 Whether this will prove a viable approach to therapy is as yet Inhibitors,research,lifescience,medical unclear. Therapies targeting tau and/or neurofibrillary tangle formation Tau, a microtubule-associated protein, is the major protein of neurofibrillary
tangles. The amyloid cascade hypothesis considers that changes in tau leading to neurofibrillary tangle formation and to be secondary events, and this viewpoint resulted in a neglect of this area in terms of therapeutics (with a few notable exceptions). A Dactolisib concentration change in perception resulted from the discover)’ of mutations in the human tau gene that caused the neurodegenerative diseases collectively called frontotemporal dementia or tauopathies.52 These diseases are characterized by massive degeneration of frontal and temporal cortex, frequently with Parkinsonian features and sometimes featuring extensive tangle pathology.53 Since the initial reports, it has become clear that a number of single amino acid changes in tau result in neuronal degeneration, and that even mutations that do not alter the amino acid sequence can cause disease, by altering the splicing of the tau mRNA.