PMID- 36895036
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230313
IS  - 2045-3701 (Print)
IS  - 2045-3701 (Electronic)
IS  - 2045-3701 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Mar 9
TI  - A novel rhein-huprine hybrid ameliorates disease-modifying properties in 
      preclinical mice model of Alzheimer's disease exacerbated with high fat diet.
PG  - 52
LID - 10.1186/s13578-023-01000-y [doi]
LID - 52
AB  - BACKGROUND: Alzheimer's disease (AD) is characterized by a polyetiological 
      origin. Despite the global burden of AD and the advances made in AD drug research 
      and development, the cure of the disease remains elusive, since any developed 
      drug has demonstrated effectiveness to cure AD. Strikingly, an increasing number 
      of studies indicate a linkage between AD and type 2 diabetes mellitus (T2DM), as 
      both diseases share some common pathophysiological features. In fact, beta-secretase 
      (BACE1) and acetylcholinesterase (AChE), two enzymes involved in both conditions, 
      have been considered promising targets for both pathologies. In this regard, due 
      to the multifactorial origin of these diseases, current research efforts are 
      focusing on the development of multi-target drugs as a very promising option to 
      derive effective treatments for both conditions. In the present study, we 
      evaluated the effect of rhein-huprine hybrid (RHE-HUP), a synthesized BACE1 and 
      AChE inhibitor, both considered key factors not only in AD but also in metabolic 
      pathologies. Thus, the aim of this study is to evaluate the effects of this 
      compound in APP/PS1 female mice, a well-established familial AD mouse model, 
      challenged by high-fat diet (HFD) consumption to concomitantly simulate a 
      T2DM-like condition. RESULTS: Intraperitoneal treatment with RHE-HUP in APP/PS1 
      mice for 4 weeks reduced the main hallmarks of AD, including Tau 
      hyperphosphorylation, Abeta(42) peptide levels and plaque formation. Moreover, we 
      found a decreased inflammatory response together with an increase in different 
      synaptic proteins, such as drebrin 1 (DBN1) or synaptophysin, and in neurotrophic 
      factors, especially in BDNF levels, correlated with a recovery in the number of 
      dendritic spines, which resulted in memory improvement. Notably, the improvement 
      observed in this model can be attributed directly to a protein regulation at 
      central level, since no peripheral modification of those alterations induced by 
      HFD consumption was observed. CONCLUSIONS: Our results suggest that RHE-HUP could 
      be a new candidate for the treatment of AD, even for individuals with high risk 
      due to peripheral metabolic disturbances, given its multi-target profile which 
      allows for the improvement of some of the most important hallmarks of the 
      disease.
CI  - (c) 2023. The Author(s).
FAU - Espinosa-Jimenez, Triana
AU  - Espinosa-Jimenez T
AD  - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of 
      Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain.
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
FAU - Cano, Amanda
AU  - Cano A
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty 
      of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.
AD  - Ace Alzheimer Center Barcelona-International University of Catalunya (UIC), 
      Barcelona, Spain.
AD  - Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 
      Barcelona, Spain.
FAU - Sanchez-Lopez, Elena
AU  - Sanchez-Lopez E
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty 
      of Pharmacy and Food Sciences, Universitat de Barcelona, Barcelona, Spain.
AD  - Institute of Nanoscience and Nanotechnology (IN2UB), Universitat de Barcelona, 
      Barcelona, Spain.
AD  - Unit of Synthesis and Biomedical Applications of Peptides, IQAC-CSIC, 08034, 
      Barcelona, Spain.
FAU - Olloquequi, Jordi
AU  - Olloquequi J
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Department of Biochemistry and Physiology, Faculty of Pharmacy and Food Sciences, 
      Universitat de Barcelona, Barcelona, Spain.
AD  - Institute of Biomedical Sciences, Faculty of Health Sciences, Universidad 
      Autonoma de Chile, Talca, Chile.
FAU - Folch, Jaume
AU  - Folch J
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Institut d'Investigacio Sanitaria Pere Virgili (IISPV), 43201, Reus, Spain.
AD  - Nutrition and Metabolic Health Research Group, Institute of Health Pere 
      Virgili-IISPV, 43201, Reus, Spain.
FAU - Bullo, Monica
AU  - Bullo M
AD  - Institut d'Investigacio Sanitaria Pere Virgili (IISPV), 43201, Reus, Spain.
AD  - Nutrition and Metabolic Health Research Group, Institute of Health Pere 
      Virgili-IISPV, 43201, Reus, Spain.
AD  - CIBER Physiology of Obesity and Nutrition (CIBEROBN), Carlos III Health 
      Institute, 28029, Madrid, Spain.
FAU - Verdaguer, Ester
AU  - Verdaguer E
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, 
      Universitat de Barcelona, Barcelona, Spain.
FAU - Auladell, Carme
AU  - Auladell C
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
AD  - Department of Cellular Biology, Physiology and Immunology, Faculty of Biology, 
      Universitat de Barcelona, Barcelona, Spain.
FAU - Pont, Caterina
AU  - Pont C
AD  - Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and 
      Food Sciences, Universitat de Barcelona, Barcelona, Spain.
FAU - Munoz-Torrero, Diego
AU  - Munoz-Torrero D
AD  - Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and 
      Food Sciences, Universitat de Barcelona, Barcelona, Spain.
AD  - Institute of Biomedicine (IBUB), Universitat de Barcelona, Barcelona, Spain.
FAU - Parcerisas, Antoni
AU  - Parcerisas A
AD  - Department of Basic Sciences, Universitat Internacional de Catalunya (UIC), Sant 
      Cugat del Valles, Spain.
FAU - Camins, Antoni
AU  - Camins A
AD  - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of 
      Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain.
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain.
FAU - Ettcheto, Miren
AU  - Ettcheto M
AUID- ORCID: 0000-0002-4301-7297
AD  - Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of 
      Pharmacy and Food Science, Universitat de Barcelona, Barcelona, Spain. 
      mirenettcheto@ub.edu.
AD  - Institute of Neuroscience, Universitat de Barcelona, Barcelona, Spain. 
      mirenettcheto@ub.edu.
AD  - Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), 
      Madrid, Spain. mirenettcheto@ub.edu.
AD  - Unitat de Farmacologia i Farmacognosia, Facultat de Farmacia i Ciencies de 
      l'Alimentacio, Universitat de Barcelona, Av. Joan XXIII 27/31, 08028, Barcelona, 
      Spain. mirenettcheto@ub.edu.
LA  - eng
GR  - SAF2017-84283-R/Ministerio de ciencias e innovacion/
GR  - PID2021-122473OA-I00/Ministerio de ciencias e innovacion/
GR  - PID2021-122187NB-C32/Ministerio de ciencias e innovacion/
GR  - PID2021-123462OB-I00/Ministerio de ciencias e innovacion/
GR  - PID2020-118127RB-I00/ministerio de ciencias e innovacion/
GR  - PI19/00854/Fondo de investigacion sanitaria/
GR  - CB06/05/0024/Centro de Investigacion Biomedica en Red sobre Enfermedades 
      Neurodegenerativas/
GR  - 2014SGR‑525/Generalitat de Catalunya/
GR  - 847879)/PRIME/H2020-SC1-BHC-2018-2020,/
GR  - CD22/00125/Salud Calos III Sara Borrell fellowship/
GR  - CEX2021-001159-M/PROGRAMA DE EXCELENCIA MARIA DE MAEZTU/
PT  - Journal Article
DEP - 20230309
PL  - England
TA  - Cell Biosci
JT  - Cell & bioscience
JID - 101561195
PMC - PMC9999531
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - BACE1
OT  - BDNF
OT  - Cognitive decline
OT  - Dendritic spines
OT  - High-fat diet
OT  - Neuroinflammation
OT  - Rhein-huprine hybrid
OT  - TLR4
OT  - Tau
COIS- The authors declare no competing interests.
EDAT- 2023/03/10 06:00
MHDA- 2023/03/10 06:01
PMCR- 2023/03/09
CRDT- 2023/03/09 23:41
PHST- 2022/12/29 00:00 [received]
PHST- 2023/02/28 00:00 [accepted]
PHST- 2023/03/09 23:41 [entrez]
PHST- 2023/03/10 06:00 [pubmed]
PHST- 2023/03/10 06:01 [medline]
PHST- 2023/03/09 00:00 [pmc-release]
AID - 10.1186/s13578-023-01000-y [pii]
AID - 1000 [pii]
AID - 10.1186/s13578-023-01000-y [doi]
PST - epublish
SO  - Cell Biosci. 2023 Mar 9;13(1):52. doi: 10.1186/s13578-023-01000-y.