AAV2/1 CD74 gene transfer reduces β-amyloidosis and improves learning and memory in a mouse model of Alzheimer's disease

Tomomi Kiyota, Gang Zhang, Christine M. Morrison, Megan E. Bosch, Robert A. Weir, Yaman Lu, Weiguo Dong, Howard E. Gendelman

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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

Original languageEnglish (US)
Pages (from-to)1712-1721
Number of pages10
JournalMolecular Therapy
Volume23
Issue number11
DOIs
StatePublished - Nov 1 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Fingerprint Dive into the research topics of 'AAV2/1 CD74 gene transfer reduces β-amyloidosis and improves learning and memory in a mouse model of Alzheimer's disease'. Together they form a unique fingerprint.

  • Cite this