AAV2/1 CD74 Gene Transfer Reduces ß-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease.
Mol Ther
; 23(11): 1712-1721, 2015 Nov.
Article
in En
| MEDLINE
| ID: mdl-26227349
ABSTRACT
Modulation of the amyloid-ß (Aß) trafficking pathway heralds a new therapeutic frontier for Alzheimer's disease (AD). As CD74 binds to the amyloid-ß precursor protein (APP) and can suppresses Aß processing, we investigated whether recombinant adeno-associated virus (AAV) delivery of CD74 could reduce Aß production and affect disease outcomes. This idea was tested in a mouse AD model. Cotransduction of AAV-tetracycline-controlled transactivator (tTA) and AAV-tet-response element (TRE)-CD74 resulted in CD74 expression, reduced Aß production in mouse neurons containing the human APP with familial AD-linked mutations. Stereotaxic injection of AAV-TRE-GFP or CD74 into the hippocampi of an AD mouse, defined as a TgCRND8 × calmodulin-dependent protein kinase II derived promoter-tTA double-transgenic, reduced Aß loads and pyramidal neuronal Aß accumulation in the hippocampus. Immunofluorescent studies showed that APP colocalization with Lamp1 was increased in CD74-expressing neurons. Moreover, Morris water maze tasks demonstrated that mice treated with AAV-TRE-CD74 showed improved learning and memory compared to AAV-TRE-GFP control animals. These results support the idea that CD74-induced alteration of Aß processing could improve AD-associated memory deficits as shown in mouse models of human disease.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Antigens, Differentiation, B-Lymphocyte
/
Histocompatibility Antigens Class II
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Amyloid beta-Protein Precursor
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Alzheimer Disease
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Neurons
Limits:
Animals
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Female
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Humans
/
Male
Language:
En
Journal:
Mol Ther
Journal subject:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Year:
2015
Document type:
Article