Impairment of ciliary dynamics in an APP knock-in mouse model of Alzheimer's disease

• Published in: Biochemical and biophysical research communications 2022-06, Vol.610, p.85-91
• Main Authors: Kobayashi, Yuki, Kohbuchi, Shogo, Koganezawa, Noriko, Sekino, Yuko, Shirao, Tomoaki, Saido, Takaomi C., Saito, Takashi, Saito, Yumiko
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Amyloid beta-Protein Precursor - genetics; Amyloid beta-Protein Precursor - metabolism; Amyloid-beta peptide; Animals; Ciliopathies; Disease Models, Animal; Hippocampus; Mice; Mice, Inbred C57BL; Mice, Transgenic; Primary cilia; Rats
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2022.04.050

The primary cilium is a specialized microtubule-based sensory organelle that extends from the cell body of nearly all cell types. Neuronal primary cilia, which have their own unique signaling repertoire, are crucial for neuronal integrity and the maintenance of neuronal connectivity throughout adulthood. Dysfunction of cilia structure and ciliary signaling is associated with a variety of genetic syndromes, termed ciliopathies. One of the characteristic features of human ciliopathies is impairment of memory and cognition, which is also observed in Alzheimer's disease (AD). Amyloid β peptide (Aβ) is produced through the proteolytic processing of amyloid precursor protein (APP), and Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of AD. To evaluate the effect of increased Aβ level on primary cilia, we assessed ciliary dynamics in hippocampal neurons in an APP knock-in AD model (AppNL-G-F mice) compared to that in wild-type mice. Neuronal cilia length in the CA1, CA3, and dentate gyrus (DG) of wild-type mice increased significantly with age. In AppNL-G-F mice, such elongation was detected in the DG but not in the CA1 and CA3, where more Aβ accumulation was observed. We further demonstrated that Aβ1-42 treatment decreased cilia length both in hTERT-RPE1 cells and dissociated rat hippocampal neurons. There is growing evidence that reduced cilia length is associated with perturbations of synaptic connectivity and dendrite complexity. Thus, our observations raise the important possibility that structural alterations in neuronal cilia might have a role in AD development. •Primary cilia length in hippocampal neuron increased with age in wild-type mice.•Cilia elongation with age was impaired in the CA1/CA3 of knock-in mouse model of AD.•Aβ1-42 treatment shortened primary cilia length in cultured rat hippocampal neurons.•Structural alterations in neuronal cilia may have a possible role in AD development.