Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS‐AD‐linked degenerative phenotypes in the Dp16 mouse model of Down syndrome DOI Creative Commons
Xu‐Qiao Chen,

Xinxin Zuo,

Ann Becker

и другие.

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation RAB5, elevated levels guanine nucleotide exchange factors (GEFs) for RABs 7 11. METHODS We investigated whether increasing dose RAB5 contributed to neuropathogenesis a clinically feasible intervention could reverse ELN changes. The Dp16 mouse model was treated with App ‐specific antisense oligonucleotide ( ‐ASO) Rab5 ASOs targeting Rab5a Rab5b . RESULTS ‐ASO treatment normalized full‐length (fl‐APP) its products, activity, downstream 11 pathways. ‐ASOs reduced restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These highlight therapeutic potential ASO‐based strategies or counteract features. Highlights products activity GEF mice. Administration were well tolerated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, synaptic protein loss. reversed established pathological phenotypes

Язык: Английский

Antisense oligonucleotides directed against App and Rab5 normalized endosomal Rab activity and reversed DS‐AD‐linked degenerative phenotypes in the Dp16 mouse model of Down syndrome DOI Creative Commons
Xu‐Qiao Chen,

Xinxin Zuo,

Ann Becker

и другие.

Alzheimer s & Dementia, Год журнала: 2025, Номер 21(5)

Опубликована: Май 1, 2025

Abstract INTRODUCTION Down syndrome (DS) markedly raises the risk of Alzheimer's disease (DS‐AD). Our findings identified widespread dysregulation endolysosomal network (ELN) in DS and DS‐AD brains, driven by increased APP gene dose, hyperactivation RAB5, elevated levels guanine nucleotide exchange factors (GEFs) for RABs 7 11. METHODS We investigated whether increasing dose RAB5 contributed to neuropathogenesis a clinically feasible intervention could reverse ELN changes. The Dp16 mouse model was treated with App ‐specific antisense oligonucleotide ( ‐ASO) Rab5 ASOs targeting Rab5a Rab5b . RESULTS ‐ASO treatment normalized full‐length (fl‐APP) its products, activity, downstream 11 pathways. ‐ASOs reduced restored endosomal Rab activity. Both ASO treatments mitigated DS‐AD‐linked pathologies. DISCUSSION These highlight therapeutic potential ASO‐based strategies or counteract features. Highlights products activity GEF mice. Administration were well tolerated APP‐linked pathologies including tau hyperphosphorylation, neurotrophin signaling deficits, synaptic protein loss. reversed established pathological phenotypes

Язык: Английский

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