AAV2/1 CD74 Gene Transfer Reduces β-amyloidosis and Improves Learning and Memory in a Mouse Model of Alzheimer's Disease

Modulation of the amyloid-beta (A beta) trafficking pathway heralds a new therapeutic frontier for Alzheimer's disease (AD). As CD74 binds to the amyloid-beta precursor protein (APP) and can suppresses A beta processing, we investigated whether recombinant adeno-associated virus (AAV) delivery of CD74 could reduce A beta 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 A beta 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 x calmodulin-dependent protein kinase II derived promoter-tTA doubletransgenic, reduced A beta loads and pyramidal neuronal A beta 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 A beta processing could improve AD-associated memory deficits as shown in mouse models of human disease.