ImmunoPEGliposome-mediated reduction of blood and brain amyloid levels in a mouse model of Alzheimer's disease is restricted to aged animals

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• 作者：Lara Ordó ; ñ ; ez-Gutié ; rrez^a ; ^b ; ¹ ; Adriá ; n Posado-Ferná ; ndez^c ; ¹ ; Davoud Ahmadvand^d ; ^e ; ¹ ; Barbara Lettiero^d ; Linping Wu^d ; Marta Antó ; n^a ; ^b ; Orfeu Flores^c ; Seyed Moein Moghimi^d ; ^f ; ^g ; ^{moein.moghimi@gmail.com" class="auth_mail" title="E-mail the corresponding author} ; Francisco Wandosell^a ; ^b ; ^{fwandosell@cbm.csic.es" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Amyloidosis ; Anti-Aβ antibody ; APP/PS1 mouse ; Immunotherapy ; Liposome
• 刊名：Biomaterials
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：112
• 期：Complete
• 页码：141-152
• 全文大小：1674 K

文摘

The accumulation of extracellular amyloid-beta (Aβ) and intracellular neurofibrillary tangles (hyper-phosphorylated Tau) in the brain are two major neuropathological hallmarks of Alzheimer's disease (AD). Active and passive immunotherapy may limit cerebral Aβ deposition and/or accelerate its clearance. With the aid of a newly characterized monoclonal anti-Aβ antibody we constructed immunoPEGliposomes with high avidity for capturing Aβ in the periphery. The functionality of these vesicles in modulating Aβ uptake by both human brain capillary endothelial hCMEC/D3 cells (suppressing uptake) and THP-1 phagocytes (stimulating uptake) was confirmed in vitro. The multivalent immunoliposomes dramatically reduced circulating and brain levels of Aβ_1-40, and particularly Aβ_1-42, in “aged” (16 month-old), but not “adult” (10 month-old) APP/PS1 transgenic mice on repeated intraperitoneal administration. Furthermore, the immunoPEGliposome-mediated reduction in amyloidosis correlated with lower levels of glial fibrillary acidic protein (GFAP) and reactive glia (GFAP-positive cells). This treatment also lowered the ratio of phosphorylated Tau to total Tau. The therapeutic efficacy of immunoliposome treatment was superior to free monoclonal antibody administration (at an equivalent antibody dose). The potential mechanisms and significance of age-dependent immunoliposome therapy in AD is discussed.