Alzheimer disease therapeutics: Focus on the disease and not just plaques and tangles

作者：Iqbal, Khalid^*; Liu, Fei; Gong, Cheng-Xin

来源：Biochemical Pharmacology, 2014, 88(4): 631-639.

DOI：10.1016/j.bcp.2014.01.002

• A beta
• Abnormal hyperphosphorylation of tau
• Plaques
• Neurofibrillary tangles
• Protein phosphatase-2A
• Neuroregeneration
• Tauopathies

The bulk of AD research during the last 25 years has been A beta-centric based on a strong faith in the Amyloid Cascade Hypothesis which is not supported by the data on humans. To date, A beta-based therapeutic clinical trials on sporadic cases of AD have been negative. Although most likely the major reason for the failure is that A beta is not an effective therapeutic target for sporadic AD, initiation of the treatment at mild to moderate stages of the disease is blamed as too late to be effective. Clinical trials on presymptomatic familial AD cases have been initiated with the logic that A beta is a trigger of the disease and hence initiation of the A beta immunotherapies several years before any clinical symptoms would be effective. There is an urgent need to explore targets other than A. There is now increasing interest in inhibiting tau pathology, which does have a far more compelling rationale than A beta. AD is multifactorial and over 99% of the cases are the sporadic form of the disease. Understanding of the various etiopathogenic mechanisms of sporadic AD and generation of the disease-relevant animal models are required to develop rational therapeutic targets and therapies. Treatment of AD will require both inhibition of neurodegeneration and regeneration of the brain.

• 出版日期2014-4-15