L-3-n-butylphthalide improves cognitive impairment and reduces amyloid-beta in a transgenic model of Alzheimer's disease.
Alzheimer's disease (AD) is an age-related, progressive neurodegenerative disorder that occurs gradually and results in memory, behavior, and personality changes. L-3-n-butylphthalide (L-NBP), an extract from seeds of Apium graveolens Linn (Chinese celery), has been demonstrated to have neuroprotective effects on ischemic, vascular dementia, and amyloid-beta (Abeta)-infused animal models. In the current study, we examined the effects of L-NBP on learning and memory in a triple-transgenic AD mouse model (3xTg-AD) that develops both plaques and tangles with aging, as well as cognitive deficits. Ten-month-old 3xTg-AD mice were given 15 mg/kg L-NBP by oral gavage for 18 weeks. L-NBP treatment significantly improved learning deficits, as well as long-term spatial memory, compared with vehicle control treatment. L-NBP treatment significantly reduced total cerebral Abeta plaque deposition and lowered Abeta levels in brain homogenates but had no effect on fibrillar Abeta plaques, suggesting preferential removal of diffuse Abeta deposits. Furthermore, we found that L-NBP markedly enhanced soluble amyloid precursor protein secretion (alphaAPPs), alpha-secretase, and PKCalpha expression but had no effect on steady-state full-length APP. Thus, L-NBP may direct APP processing toward a non-amyloidogenic pathway and preclude Abeta formation in the 3xTg-AD mice. The effect of l-NBP on regulating APP processing was further confirmed in neuroblastoma SK-N-SH cells overexpressing wild-type human APP(695) (SK-N-SH APPwt). L-NBP treatment in 3xTg-AD mice also reduced glial activation and oxidative stress compared with control treatment. L-NBP shows promising preclinical potential as a multitarget drug for the prevention and/or treatment of Alzheimer's disease.
Peng
Ying
Y
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
Sun
Jing
J
Hon
Stephanie
S
Nylander
Alyssa N
AN
Xia
Weiming
W
Feng
Yipu
Y
Wang
Xiaoliang
X
Lemere
Cynthia A
CA
D051722:ADAM Proteins / Q000378:metabolism; D000544:Alzheimer Disease / Q000150:complications / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001572:Benzofurans / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003072:Cognition Disorders / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008297:Male; D008301:Maleimides / Q000494:pharmacology; D008315:Malondialdehyde / Q000378:metabolism; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009447:Neuroblastoma / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D018384:Oxidative Stress / Q000187:drug effects; D053764:Presenilin-1 / Q000235:genetics; D011930:Reaction Time / Q000187:drug effects; D013037:Spatial Behavior / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016875:tau Proteins / Q000235:genetics
D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D001572:Benzofurans; D004791:Enzyme Inhibitors; D007211:Indoles; D008301:Maleimides; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016875:tau Proteins; D008315:Malondialdehyde; C027125:3-n-butylphthalide; D017493:Leukocyte Common Antigens; D051722:ADAM Proteins; C070515:bisindolylmaleimide I