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

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.

Viral vectors for therapy of neurologic diseases

“…Alternatively, targeting the cleavage of APP has been attempted, with genetic transfer of siRNA specific for β-secretase (Nawrot, 2004) or shRNA to knock-down the orphan G protein-coupled receptor that regulates activity of γ-secretase (Huang et al, 2015a), the first and second enzymes, respectively, controlling the proteolysis of APP to produce the neurotoxic amyloid peptides, respectively. Additionally, AAV-mediated expression of CD74, a chaperone that directly binds to the APP, also prevents the accumulation of Aβ in the hippocampus and improves cognitive deficits of AD mice (Kiyota et al, 2015). …”

High-fat diet impairs cognitive function of zebrafish

“…In addition, increased levels of appb and psen1 mRNA, and decreased levels of cd74a, cd74b, and ece1 mRNA in telencephalon were observed in HF diet-fed zebrafish. These changes in gene expression are considered to accelerate the production and suppress the degradation of amyloid-β protein in the brain of mammals 45,46 . Many reports show that amyloid-β protein is increased in the brain of HF diet-fed rodents with cognitive dysfunction [47][48][49] .…”

Identifying and ranking potential driver genes of Alzheimer’s Disease using multi-view evidence aggregation

“…We observe that global network topological features from inferred sparse coexpression networks -such as node degree -are predictive of LOAD driver genes as identified in GWAS, and more so than differential expression features. Finally, we show that our ranking methodology identifies several previously known LOAD loci implicated in other studies (Mukherjee et al, 2017;Ki et al, 2002;Kiyota et al, 2015;Jonsson et al, 2013) as well potentially new LOAD risk loci. These findings may lead to new mechanistic hypotheses regarding the genetic drivers of LOAD.…”

“…Having demonstrated the statistical significance of the predicted driver genes, we ranked them using our ranking schema. The top 20 ranked genes can be seen in Table 2, which contains several genes strongly linked with AD such as APOE, APOC1, CD74, TREM2, SLC7A7 (Mukherjee et al, 2017;Ki et al, 2002;Kiyota et al, 2015;Jonsson et al, 2013) etc.. Table 2 also contains the minimum SNP p-values for each of these genes according to the IGAP and Jansen studies. It can be seen that while our models are not trained on any SNP information, the results strongly align with additional validation GWAS data.…”