Abnormal accumulation of extracellular vesicles in hippocampal dystrophic axons and regulation by the primary cilia in Alzheimer’s disease

• Published in: Acta neuropathologica communications 2023-09, Vol.11 (1), p.1-30, Article 142
• Main Authors: Jang, Jaemyung, Yeo, Seungeun, Baek, Soonbong, Jung, Hyun Jin, Lee, Mi Suk, Choi, Seung Hee, Choe, Youngshik
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer's disease; Animals; Brain research; Dystrophic neurites; E coli; Ethics; Extracellular vesicles; Hippocampal septal connection; Neurons; Neurophysiology; Plasmids; Primary cilia; Research centers; RNA sequencing; Selectively vulnerable neurons; Single cell RNA sequencing; Three dimensional imaging
• ISSN: 2051-5960; 2051-5960
• DOI: 10.1186/s40478-023-01637-3

Dystrophic neurites (DNs) are abnormal axons and dendrites that are swollen or deformed in various neuropathological conditions. In Alzheimer's disease (AD), DNs play a crucial role in impairing neuronal communication and function, and they may also contribute to the accumulation and spread of amyloid beta (A[beta]) in the brain of AD patients. However, it is still a challenge to understand the DNs of specific neurons that are vulnerable to A[beta] in the pathogenesis of AD. To shed light on the development of radiating DNs, we examined enriched dystrophic hippocampal axons in a mouse model of AD using a three-dimensional rendering of projecting neurons. We employed the anterograde spread of adeno-associated virus (AAV)1 and conducted proteomic analysis of synaptic compartments obtained from hippocampo-septal regions. Our findings revealed that DNs were formed due to synaptic loss at the axon terminals caused by the accumulation of extracellular vesicle (EV). Abnormal EV-mediated transport and exocytosis were identified in association with primary cilia, indicating their involvement in the accumulation of EVs at presynaptic terminals. To further address the regulation of DNs by primary cilia, we conducted knockdown of the Ift88 gene in hippocampal neurons, which impaired EV-mediated secretion of A[beta] and promoted accumulation of axonal spheroids. Using single-cell RNA sequencing, we identified the septal projecting hippocampal somatostatin neurons (SOM) as selectively vulnerable to A[beta] with primary cilia dysfunction and vesicle accumulation. Our study suggests that DNs in AD are initiated by the ectopic accumulation of EVs at the neuronal axon terminals, which is affected by neuronal primary cilia. Graphical abstract Keywords: Dystrophic neurites, Primary cilia, Hippocampal septal connection, Extracellular vesicles, Single cell RNA sequencing, Selectively vulnerable neurons