Age is the most important risk factor for Alzheimer's disease (AD), but the occurrence of this disease is
also affected by environmental factors, individual experience and genetic pre-deposition. Genetic factors are
well established to play an important role in risk of AD. CELF2, an RNA binding protein that regulates
alternative splicing and RNA stability, has been recently identified as a risk factor associated with AD.
Polymorphisms in CELF2 are significantly associated with high-risk alleles of APOE, and the “A” allele of SNP
rs2242451 is associated with reduced AD risk. CELF2 is highly expressed in the nervous system, and
enhanced neuronal CELF2 expression levels have been found in various neurodegeneration models and
human patients. We generated a conditional knockout mouse Celf2 allele. Our preliminary data suggest that
deleting Celf2 in adult brain has beneficial effects, including improved learning and memory. We identified
mRNA targets of mouse CELF2 (using CLIP-seq; cross-linking immunoprecipitation high-throughput
sequencing) and found that CELF2 binds to introns around the alternatively spliced exons of a set of AD-
regulated genes, including APP, MAPT (Tau), PSEN1, PSEN2, and BIN1, suggesting a key role of CELF2 in
regulating alternative splicing of AD-related genes. Alternative splicing of these AD-related genes is known to
regulate AD pathogenesis. For example, alternative splicing of exon 10 of the tau mRNA gives rise to protein
isoforms with three (3R) or four (4R) microtubule binding repeats. Imbalances in 4R: 3R ratio alone have been
reported sufficient to induce the pathogenesis of AD in a human-Tau mouse model. Taken together with the
genetic association between CELF2 SNP and reduced AD risk in humans, we hypothesize that CELF2
expression is up-regulated in AD brains and loss of CELF2 in adult brains is sufficient to rescue AD-related
phenotypes. In Specific Aim 1, we will test whether loss of CELF2 can suppress AD-related phenotypes in C.
elegans AD models. In Specific Aim 2, we will test whether loss of CELF2 in the adult brain is protective
through regulating alternative splicing using AD mouse models. In Specific Aim 3, we will test whether CELF2
expression is increased in AD brains using postmortem human samples and ask if the AD risk-reducing SNP
down regulates CELF2 expression or inhibits its function using human iPSC-derived neurons. We have
obtained postmortem brain samples and established a strong research team with expertise in genetics,
genomics, postmortem AD brains and iPSC. Data from the proposed work will provide important mechanistic
insights that go well beyond published human genetic analyses and ultimately yield new therapeutic targets for
the treatment of AD.