Table 1.
Major observations of primary cilia and ciliary signaling in age-related diseases.
| Disease | Model | Alteration of primary cilia (length, frequency, fragment) | Methods (Marker) | Ciliary Signaling | Therapeutic attempt | Reference |
|---|---|---|---|---|---|---|
| AD | 3xAD-transgenic mice | Decreased in the number of HH3 positive cells with age and in AD mice | Immunostaining for HH3 | NA | NA | (Rodriguez et al.,2008) |
| 3xAD-transgenic mice | Reduction in length of primary cilia in the hippocampal dentate gyral cells | Immunostaining for SSTR3 and p75NTR | NA | NA | (Chakravarthy et al., 2012) | |
| hfNBMs | NGF treatment increased the percentage of cells exhibiting primary cilium | Immunostaining for acetylated α-tubulin | NA | Intravenous administration of hfNBMs improved memory functions in AD rats | (Morelli et al., 2017) | |
| Mouse NIH3T3 and human HeLa cells | Amyloid-β decreased primary cilia length and frequency | Immunostaining for acetylated α-tubulin | SHH | Inhibition of Aβ production rescued the cilia morphological changes | (Vorobyeva and Saunders, 2018) | |
| APP/PS1 mice | Elongated in the hippocampus of APP/PS1 mice | Immunostaining for AC3 and ARL13B | NA | 5-HT6 antagonist SB271046 rescued the cognitive impairment in APP/PS1 mice | (Hu et al., 2017) | |
| J20-APP transgenic mice | NA | NA | Wnt signaling | NA | (Tapia-Rojas and Inestrosa, 2018) | |
| APP/PS1 mice | NA | NA | Wnt/β-catenin signaling | intra-hippocampal administration of WASP-1 rescues hippocampal synaptic impairments | (Vargas et al., 2015) | |
| SAMP8 mice | NA | NA | Downregulation of Wnt signaling in the hippocampus | NA | (Bayod et al., 2015) | |
| APP/PS1 mice | NA | NA | Notch | SP600125 treatment reverses AD Phenotypes | (Rahman et al., 2012; Zhou et al., 2015) | |
| APP/PS1 mice | NA | NA | Notch | Intragastrical administration of curcumin promoted proliferation of adult neural stem cells and birth of neurons and ameliorated cognitive impairment | (Li et al., 2019) | |
| AD patients | NA | NA | Elevated levels of TGFβ in the CSF and serum | NA | (Chao et al., 1994b) | |
| Human glioblastoma cells | NA | NA | TGFβ bound to βAPP | NA | (Bodmer et al., 1990) | |
| Human-APP transgenic mice | NA | NA | Overexpression of TGFβ accelerated the deposition of Aβ | TGFβ could promote amyloidogenesis | (Wyss-Coray et al., 1997) | |
| Human-APP transgenic mice | NA | NA | TGFβ | TGFβ reduces amyloid plaque burden | (Wyss-Coray et al., 2001) | |
| AβOs administered mice | NA | NA | TGFβ | Astrocyte-derived TGFβ protects synapses against AβOs | (Diniz et al., 2017) | |
| PD | 6-OHDA-lesioned rats | Elongated primary cilia in striatal neurons | Immunostaining for AC3 | NA | Bromocriptine administration abrogates the elongation of striatal neuronal cilia in lesioned sides of hemiparkinsonian rats. | (Miyoshi et al., 2014) |
| LRRK2-R1441C MEFs and LRRK2-G2019S expressing 3 T3 fibroblasts | Hyperactive LRRK2 decreased primary ciliogenesis | Immunostaining for ARL13B | NA | NA | (Steger et al., 2017) | |
| Human LRRK2 G2019S iPS cells and LRRK2 R1441C mice | LRRK2 kinase interferes with primary ciliogenesis | Immunostaining for ARL13B in vitro and AC3 & SSTR3 in vivo. | SHH | NA | (Dhekne et al., 2018) | |
| Mice model of MPTP-induced PD | Enhanced ciliogenesis in the substantia nigra dopamine neurons | Immunostaining for AC3 | NA | MPTP-induced primary ciliogenesis was significantly reduced in IFT88 shRNA-expressing neurons | (Bae et al., 2019) | |
| 6-OHDA-induced rat model of PD | NA | NA | SHH | Intrastriatal administration of SHH rescues behavioral impairment | (Tsuboi and Shults, 2002) | |
| 6-OHDA-induced rat model of PD | NA | NA | SHH | gene transfer of SHH and GLI1protect dopaminergic nigrostriatal neuronal cell bodies from a specific neurotoxic insult | (Hurtado-Lorenzo et al., 2004) | |
| 6-OHDA-induced rat model of PD | NA | NA | Wnt antagonist - Dkk1 is upregulated | LiCl, an inhibitor of GSK-3β, rescues the Wnt signaling pathway in the ventral midbrain of 6-OHDA PD rats | (Dun et al., 2012) | |
| 6-OHDA-induced rat model of PD | NA | NA | Wnt | LiCl administration restored motor function and memory | (Qi et al., 2017) | |
| RenVm cells | NA | NA | Wnt | LiCl facilitates dopaminergic differentiation | (Soleimani and Ghasemi, 2017) | |
| α-syn Tg mice | NA | NA | Notch | NA | (Crews et al., 2008) | |
| Mouse embryos e transfected with LRRK2 plasmid | NA | NA | Suppression of Notch signaling accelerated neuronal differentiation | NA | (Imai et al., 2015) | |
| MPTP-induced mouse model of PD | NA | NA | Notch | Administration of osthole attenuates motor deficits | (Wang et al., 2019) | |
| αSO injected mice (intracerebroventricular) | NA | NA | TGFβ | TGFβ promotes glutamatergic synapse formation in the striatum of parkinsonian animals | (Diniz et al., 2019) | |
| ALS | G93A SOD1 (mSOD) mice | The proportion of ciliated neurons is reduced | Immunostaining for AC3 | NA | NA | (Ma et al., 2011) |
| HT22 cells transfected with wtSOD, mSOD, or empty vector | NA | NA | SHH | SHH or the SHH agonist PUR reduces cell death | (Peterson and Turnbull, 2012) | |
| Cell cultures derived from wild type or mSOD1 mice | SHH increased the number of ciliated motor neurons in culture | Immunostaining for AC3 | SHH | SHH increased the percentage of ciliated motor neurons, especially in mSOD1 culture | (Ma et al., 2013) | |
| mSOD mice and Shh Light II cells | NA | NA | Notch (reduced in motor neurons and increased in astroglia) | NA | (Ma et al., 2017) | |
| SOD1* mice | NA | NA | Notch | AGT251 increases survival of SOD1* mice | (von Grabowiecki et al., 2015) | |
| mSOD mice | NA | NA | Wnt is upregulated in the spinal cord astrocytes | NA | (Chen et al., 2012a) | |
| NSC34hSOD1G93A cells | NA | NA | Wnt is downregulated neuron-like cells | NA | (Pinto et al., 2013) | |
| Human ALS spinal cord | NA | NA | Wnt | NA | (Gonzalez-Fernandez et al., 2019) | |
| SOD1(G93A) mice | NA | NA | Astrocyte-derived TGFβ1 accelerates disease progression | TGFβ signaling inhibitor extends the survival time of ALS mice | (Endo et al., 2015) | |
| SOD1(G93A) mice | NA | NA | TGFβ | ActRIIB.mFc increases muscle mass and myofiber diameter | (Morrison et al.,2009) | |
| Stroke | Endothelial cells | NA | Immunostaining for acetylated α-tubulin | NA | ECs lacking primary cilia show increased mineralization in response to BMP-6 | (Sanchez-Duffhues et al., 2015) |
| Apoe−/− mice | NA | Immunostaining for ARL13B | NA | Loss of primary cilia in ECs induces atherosclerosis | (Dinsmore and Reiter, 2016) | |
| MCAO stroke mice | NA | NA | SHH | Intravenous PUR attenuates neuroinflammation and promotes regeneration | (Chechneva et al., 2014) | |
| Hypoxic-ischemic mice | NA | NA | SHH | PUR protects against neuronal damage and brain injury in acute experimental ischemic stroke | (Liu et al., 2020b) | |
| MCAO stroke rats | NA | NA | SHH | BMSC treatment improves neurological outcomes via activating the Shh/Gli1 signaling pathway | (Zhang et al.,2009) | |
| MCAO stroke rats | NA | NA | SHH | Intrathecal SHH protein improves neurological recovery and stimulates neural progenitor cell proliferation | (Bambakidiset al., 2012) | |
| MCAO stroke rats | NA | NA | SHH | Intracerebroventricular SHH protein promotes angiogenesis | (Chen et al., 2017a) | |
| MCAO and doubleridge mice | NA | NA | Wnt | Inhibition of the Wnt antagonist protects neurons | (Mastroiacovo et al., 2009) | |
| ET-1 induced focal ischemic injury in mice | NA | NA | Wnt | Overexpression of Wnt3a enhances neurogenesis and improves neurological function after focal ischemic injury | (Shruster et al., 2012) | |
| MCAO | NA | NA | Notch | Inhibition of Notch signaling promotes neuronal regeneration after stroke | (Arumugam et al., 2006) | |
| VAM and Notch4*-Tet mice | NA | NA | Endothelial Notch-1 signaling is upregulated | NA | (Murphy et al., 2008) | |
| I/R rats | NA | NA | TGFβ | Administration of Sb505124, an ALK5 inhibitor, protected rats against I/R injury | (Lou et al., 2018) | |
| Ast-Tbr2DN MCAO mice | NA | NA | Ast-Tbr2DN mice exhibit a global reduction in TGFβ signaling after stroke | Inhibiting astrocytic TGFβ signaling worsens motor outcomes during the first week after stroke | (Cekanaviciute et al., 2014) |
NA: Not available; HH3: phosphorylated Histone H3, a proliferating mitotic marker; SSTR3: somatostatin receptor 3; p75NTR: p75 neurotrophin receptor; AC3: Adenylyl Cyclase type 3; hfNBMs: human fetal nucleus basalis of Meynert cells; NGF: nerve growth factor; APP/PS1 mice: double transgenic APPswe/PS1dE9 mice; MPTP: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mSOD: G93A SOD1; wtSOD: human wild type SOD1; SOD1* mice: FVB transgenic mice expressing the missense mutation G86R (human G85R equivalent) in the SOD1 gene; NSC34hSOD1G93A cells: motor neuron-like NSC34 cells that stably express human mutant SOD1; ECs: Endothelial cells; BMP-6: bone morphogenetic protein-6; PUR: Purmorphamine, an agonist of the Smoothened (Smo) receptor; MCAO: middle cerebral artery occlusion; BMSC: bone marrow stromal cell; ET-1: endothelin-1; MEFs: mouse embryonic fibroblasts; 6-OHDA: 6-hydroxydopamine; Dkk1: Dickkopf-1; α-syn Tg mice: Transgenic mice expressing human A53T mutant α-syn; VAM: Brain arteriovenous malformations; I/R: ischemia-reperfusion.