Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 mouse model.
Qihui ZhouNikola MareljicMeike MichaelsenSamira ParhizkarSteffanie HeindlBrigitte NuscherDaniel FarnyMareike CzuppaCarina SchludiAlexander GrafStefan KrebsHelmut BlumRegina FeederleStefan RothChristian HaassThomas ArzbergerArthur LieszDieter EdbauerPublished in: EMBO molecular medicine (2019)
The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)149 -CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)149 -CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)10 conjugates and pre-aggregated carrier-free (GA)15 . Only ovalbumin-(GA)10 immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)10 immunization largely rescued the motor function in (GA)149 -CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)10 -immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers.
Keyphrases
- pet ct
- amyotrophic lateral sclerosis
- mouse model
- traumatic brain injury
- gene expression
- type diabetes
- adipose tissue
- poor prognosis
- mass spectrometry
- metabolic syndrome
- cell death
- spinal cord
- skeletal muscle
- blood brain barrier
- long non coding rna
- high fat diet induced
- genome wide
- single molecule
- copy number
- cerebrospinal fluid
- lps induced
- stress induced
- cancer therapy
- high glucose