| First Author | Leitão ADG | Year | 2023 |
| Journal | Neurobiol Dis | Volume | 186 |
| Pages | 106285 | PubMed ID | 37690676 |
| Mgi Jnum | J:340741 | Mgi Id | MGI:7530544 |
| Doi | 10.1016/j.nbd.2023.106285 | Citation | Leitao ADG, et al. (2023) Novel systemic delivery of a peptide-conjugated antisense oligonucleotide to reduce alpha-synuclein in a mouse model of Alzheimer's disease. Neurobiol Dis 186:106285 |
| abstractText | Neurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as alpha-synuclein (alpha-syn) and amyloid beta (Abeta). Misfolded and aggregated alpha-syn has been implicated in neurological disorders such as Parkinson's disease, and Dementia with Lewy Bodies, but less so in Alzheimer's Disease (AD), despite the fact that accumulation of alpha-syn has been confirmed in over 50% of postmortem brains neuropathologically diagnosed with AD. To date, no therapeutic strategy has effectively or consistently downregulated alpha-syn in AD. Here we tested the hypothesis that by using a systemically-delivered peptide (ApoB(11)) bound to a modified antisense oligonucleotide against alpha-syn (ASO-alpha-syn), we can downregulate alpha-syn expression in an AD mouse model and improve behavioral and neuropathologic phenotypes. Our results demonstrate that monthly systemic treatment with of ApoB(11):ASO alpha-syn beginning at 6 months of age reduces expression of alpha-synuclein in the brains of 9-month-old AD mice. Downregulation of alpha-syn led to reduction in Abeta plaque burden, prevented neuronal loss and astrogliosis. Furthermore, we found that AD mice treated with ApoB(11):ASO alpha-syn had greatly improved hippocampal and spatial memory function in comparison to their control counterparts. Collectively, our data supports the reduction of alpha-syn through use of systemically-delivered ApoB(11):ASO alpha-syn as a promising future disease-modifying therapeutic for AD. |
