Blocking miR-33 Reduces Aβ Levels in Mice

Blocking miR-33 Reduces Aβ Levels in Mice

The strongest genetic risk factor for Alzheimer's disease (AD) is possession of an ϵ4 allele of apolipoprotein E (ApoE). Like other apolipoproteins, ApoE transports lipids and removes excess cholesterol from cells. It also interacts with β-amyloid (Aβ), the peptide fragment that promotes synaptic loss and neurodegeneration in AD, and it is thought to facilitate Aβ clearance. The ϵ4 allele appears to perform ApoE functions less efficiently than other alleles, and this likely underlies its association with AD.

Interactions between ApoE and Aβ are enhanced when ApoE is loaded with lipids. Therefore, ATP-binding cassette transporter A1 (ABCA1), a protein that transfers intracellular lipids to ApoE, also influences Aβ clearance. Specifically, loss of ABCA1 increases Aβ accumulation, whereas ABCA1 overexpression decreases Aβ accumulation. Although these effects may stem solely from ABCA1's role in ApoE lipidation, ABCA1 has also been hypothesized to limit Aβ generation by inhibiting amyloidogenic cleavage of amyloid precursor protein (APP).

In peripheral tissues, ABCA1 levels are regulated partly by microRNAs such as miR-33, which binds to ABCA1 mRNA and prevents translation. Scientists in the Journal of Neuroscience report that miR-33 also regulates ABCA1 expression in the brain. miR-33 was found in neurons and glia throughout the brain, and knocking out miR-33 not only increased ABCA1 levels, but also increased the size of ApoE-containing lipoprotein particles, suggesting ApoE lipidation was enhanced. In contrast, treating neuroblastoma cells or astrocytes with synthetic miR-33 decreased ABCA1 levels and reduced cholesterol efflux from cells.

Importantly, miR-33-dependent downregulation of ABCA1 and ApoE lipidation resulted in increased production of Aβ by neuroblastoma cells expressing an AD-linked form of APP, and it also reduced Aβ clearance from cultured cells. Conversely, Aβ degradation was greater in cortical tissue homogenates from mir-33-deficient mice than in control tissue. Moreover, intracerebroventricular delivery of an antisense oligonucleotide of miR-33 increased cortical ABCA1 levels and reduced cortical levels of Aβ in a mouse model of AD.

These results support the hypothesis that ABCA1-dependent lipidation of ApoE promotes Aβ clearance, and they indicate that this pathway can be enhanced by reducing levels of miR-33. It will be important to determine whether miR-33 reduction slows cognitive impairment in AD-model mice. If it does, finding ways to reduce miR-33 in human brain may lead to an effective treatment for AD.