Multifunctional liposomes delay phenotype progression and prevent memory impairment in a presymptomatic stage mouse model of Alzheimer disease

ABSTRACT The failure of clinical trials largely focused on mild to moderate stages of Alzheimer disease has suggested to the scientific community that the effectiveness of Amyloid‐&bgr; (A&bgr;)‐centered treatments should be evaluated starting as early as possible, well before irreversible brain damage has occurred. Accordingly, also the preclinical development of new therapies should be carried out taking into account this suggestion. In the present investigation we evaluated the efficacy of a treatment with liposomes multifunctionalized for crossing the blood‐brain barrier and targeting A&bgr;, carried out on young APP/PS1 Tg mice, taken as a model of pre‐symptomatic disease stage. Liposomes were administered once a week to Tg mice for 7 months, starting at the age of 5 months and up to the age of 12 when they display AD‐like cognitive and brain biochemical/anatomical features. The treatment prevented the onset of the long‐term memory impairment and slowed down the deposition of brain A&bgr;; at anatomical level, prevented both ventricle enlargement and entorhinal cortex thickness reduction, otherwise occurring in untreated mice. Strikingly, these effects were maintained 3 months after treatment discontinuation. An increase of A&bgr; levels in the liver was detected at the end of the treatment, then followed also by reduction of brain Amyloid Precursor Protein and increase of A&bgr;‐degrading enzymes. These results suggest that the treatment promotes brain A&bgr; clearance by a peripheral ‘sink’ effect and ultimately affects A&bgr; turnover in the brain. Worth of note, the treatment was apparently not toxic for all the organs analyzed, in particular for brain, as suggested by the lower brain TNF‐&agr; and MDA levels, and by higher level of SOD activity in treated mice. Together, these findings promote a very early treatment with multi‐functional liposomes as a well‐tolerated nanomedicine‐based approach, potentially suitable for a disease‐modifying therapy of AD, able to delay or prevent relevant features of the disease.