The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (-20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (A beta) (-37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (-36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (-66% and -31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by A beta (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (-41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (-39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (-29%; p < 0.05) and increased the A beta-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with A beta, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease / Papotti, B.; Adorni, M. P.; Marchi, C.; Zimetti, F.; Ronda, N.; Panighel, G.; Lupo, M. G.; Vilella, A.; Giuliani, D.; Ferri, N.; Bernini, F.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:20(2022), pp. 12192-12210. [10.3390/ijms232012192]

PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease

Vilella A.;Giuliani D.;Bernini F.
2022

Abstract

The Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) involvement in Alzheimer's disease (AD) is poorly investigated. We evaluated the in vitro PCSK9 modulation of astrocyte cholesterol metabolism and neuronal cholesterol supplying, which is fundamental for neuronal functions. Moreover, we investigated PCSK9 neurotoxic effects. In human astrocytoma cells, PCSK9 reduced cholesterol content (-20%; p < 0.05), with a greater effect in presence of beta amyloid peptide (A beta) (-37%; p < 0.01). PCSK9 increased cholesterol synthesis and reduced the uptake of apoE-HDL-derived cholesterol (-36%; p < 0.0001), as well as the LDL receptor (LDLR) and the apoE receptor 2 (ApoER2) expression (-66% and -31%, respectively; p < 0.01). PCSK9 did not modulate ABCA1- and ABCG1-cholesterol efflux, ABCA1 levels, or membrane cholesterol. Conversely, ABCA1 expression and activity, as well as membrane cholesterol, were reduced by A beta (p < 0.05). In human neuronal cells, PCSK9 reduced apoE-HDL-derived cholesterol uptake (-41%; p < 0.001) and LDLR/apoER2 expression (p < 0.05). Reduced cholesterol internalization occurred also in PCSK9-overexpressing neurons exposed to an astrocyte-conditioned medium (-39%; p < 0.001). PCSK9 reduced neuronal cholesterol content overall (-29%; p < 0.05) and increased the A beta-induced neurotoxicity (p < 0.0001). Our data revealed an interfering effect of PCSK9, in cooperation with A beta, on brain cholesterol metabolism leading to neuronal cholesterol reduction, a potentially deleterious effect. PCSK9 also exerted a neurotoxic effect, and thus represents a potential pharmacological target in AD.
2022
11-ott-2022
23
20
12192
12210
PCSK9 Affects Astrocyte Cholesterol Metabolism and Reduces Neuron Cholesterol Supplying In Vitro: Potential Implications in Alzheimer’s Disease / Papotti, B.; Adorni, M. P.; Marchi, C.; Zimetti, F.; Ronda, N.; Panighel, G.; Lupo, M. G.; Vilella, A.; Giuliani, D.; Ferri, N.; Bernini, F.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1422-0067. - 23:20(2022), pp. 12192-12210. [10.3390/ijms232012192]
Papotti, B.; Adorni, M. P.; Marchi, C.; Zimetti, F.; Ronda, N.; Panighel, G.; Lupo, M. G.; Vilella, A.; Giuliani, D.; Ferri, N.; Bernini, F.
File in questo prodotto:
File Dimensione Formato  
ijms-23-12192-v3.pdf

Open access

Tipologia: Versione pubblicata dall'editore
Dimensione 3.32 MB
Formato Adobe PDF
3.32 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1300945
Citazioni
  • ???jsp.display-item.citation.pmc??? 9
  • Scopus 10
  • ???jsp.display-item.citation.isi??? 9
social impact