Towards Disease-Modifying Treatment of Alzheimers Disease: Drugs Targeting β -Amyloid

Abstract

Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of beta-amyloid (Abeta) peptides may cause Alzheimer's disease (AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Abeta have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, beta-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of gamma-secretase, the protease that regulates the last metabolic step generating Abeta, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Abeta aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Abeta approaches in clinical testing, we will know in few years if the Abeta hypothesis of AD is correct.

Therapeutic targets of brain insulin resistance in sporadic Alzheimer's disease

“…To inhibit abnormal processing of AβPP and accumulation of toxic AβPP-Aβ, gamma secretases have been targeted (205, 206). Although this approach seems promising for lowering plasma, CSF, and brain AβPP-Aβ burden (203, 207), the objective clinical therapeutic responses have been minimal or undetectable (205, 208, 209). Worse yet, these drugs are highly toxic due to concurrent inhibition of Notch signaling (203, 206), which mediates neuronal plasticity, cognition, and long-term memory (210).…”

Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction

“…Scientists are exploring a number of strategies to block Aβ including “secretase inhibitors” to block the secretase clipping action [25-32]. It is not yet clear that any of these compounds will improve AD symptoms or protect neuronal cells, and none have entered clinical trials due to continuing concerns about side effects.…”

Immunotherapeutic efficiency of a tetravalent Aβ1-15 vaccine in APP/PS1 transgenic mice as mouse model for Alzheimer’s disease

“…15 During the last decade, most of The 4aβ1-15-treated aPP/Ps1 mice had a shorter swimming length before escaping onto the hidden platform on the third and fourth day (n = 9, * # p < 0.01 by aNOVa). (E) In the probe trial on the sixth day, the 4aβ15-treated mice traveled into the third quadrant, where the hidden platform was previously placed, significantly more times than controls (n = 9, *p < 0.01 by student's t-test).…”