Recent Advances in Drug Delivery Systems Targeting Insulin Signalling for the Treatment of Alzheimer’s Disease

Article type: Review Article

Authors: Sachdeva, Punya^{a; b; 1} | Narayanan, Kannan Badri^{c; d; 1} | Sinha, Jitendra Kumar^{a; *} | Gupta, Saurabh^e | Ghosh, Shampa^a | Singh, Krishna Kumar^f | Bhaskar, Rakesh^{c; d} | Almutary, Abdulmajeed G.^g | Zothantluanga, James H.^h | Kotta, Kranthi Kumarⁱ | Nelson, Vinod Kumar^j | Paiva-Santos, Ana Cláudia^{k; l} | Abomughaid, Mosleh Mohammad^m | Kamal, Mehnazⁿ | Iqbal, Danish^o | ALHarbi, Mohammed Hamoud^p | ALMutairi, Awadh Aedh^q | Dewanjee, Saikat^r | Nuli, Mohana Vamsi^j | Vippamakula, Shanmugam^s | Jha, Saurabh Kumar^t | Ojha, Shreesh^{u; *} | Jha, Niraj Kumar^{v; w; x; y; *}

Affiliations: [a] GloNeuro, Noida, Uttar Pradesh, India | [b] Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University, Noida, Uttar Pradesh, India | [c] School of Chemical Engineering, Yeungnam University, Gyeongsan, Republic of Korea | [d] Research Institute of Cell Culture, Yeungnam University, Gyeongsan, Republic of Korea | [e] Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India | [f] Symbiosis Centre for Information Technology, Rajiv Gandhi InfoTech Park, Hinjawadi, Pune, Maharashtra, India | [g] Department of Biomedical Sciences, College of Health Sciences, Abu Dhabi University, Abu Dhabi, United Arab Emirates | [h] Department of Pharmaceutical Sciences, Faculty of Science and Engineering, Dibrugarh University, Dibrugarh, Assam, India | [i] College of Pharmaceutical Sciences, Dayananda Sagar University, Bengaluru, Karnataka, India | [j] Raghavendra Institute of Pharmaceutical Education and Research, Anantapur, India | [k] Department of Pharmaceutical Technology, Faculty of Pharmacy of the University of Coimbra, University of Coimbra, Coimbra, Portugal | [l] Faculty of Pharmacy of the University of Coimbra, REQUIMTE/LAQV, Group of Pharmaceutical Technology, University of Coimbra, Coimbra, Portugal | [m] Department of Medical Laboratory Sciences, College of Applied Medical Sciences, University of Bisha, Bisha, Saudi Arabia | [n] Department of Pharmaceutical Chemistry, College of Pharmacy, Prince Sattam Bin Abdulaziz University, Al-Kharj, Saudi Arabia | [o] Department of Health Information Management, College of Applied Medical Sciences, Buraydah Private Colleges, Buraydah, Saudi Arabia | [p] Department of Infection Control, Senior Consultant of Public Health, King Khalid Hospital, Al Majmaah, Ministry of Health, Saudi Arabia | [q] Department of Medical Laboratory Sciences, College of Applied Medical Sciences, Majmaah University, Al Majmaah, Saudi Arabia | [r] Department of Pharmaceutical Technology, Advanced Pharmacognosy Research Laboratory, Jadavpur University, Kolkata, India | [s] MB School of Pharmaceutical Sciences, Mohan Babu University, A. Rangampet, Tirupati, India | [t] Department of Zoology, Kalindi College, University of Delhi, Delhi, India | [u] Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates | [v] Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India | [w] Centre of Research Impact and Outcome, Chitkara University, Rajpura, Punjab, India | [x] School of Bioengineering and Biosciences, Lovely Professional University, Phagwara, India | [y] Department of Biotechnology, School of Applied and Life Sciences (SALS), Uttaranchal University, Dehradun, India

Correspondence: [*] Correspondence to: Dr. Niraj Kumar Jha, Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India. E-mail: [email protected]; ORCID: https://orcid.org/0000-0001-9486-4069 and Dr. Jitendra Kumar Sinha, Chief Scientific Officer, GloNeuro, Sector 107, Vishwakarma Road, Noida, Uttar Pradesh 201301 India. Tel.: +91 8919679822; E-mail: [email protected]; E-mail: [email protected]; ORCID: https://orcid.org/0000-0002-7444-6932 and Dr. Shreesh Ojha, Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain P.O. Box 15551, United Arab Emirates.

Note: [1] These authors contributed equally to this work.

Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of neurofibrillary tangles and amyloid-β plaques. Recent research has unveiled the pivotal role of insulin signaling dysfunction in the pathogenesis of AD. Insulin, once thought to be unrelated to brain function, has emerged as a crucial factor in neuronal survival, synaptic plasticity, and cognitive processes. Insulin and the downstream insulin signaling molecules are found mainly in the hippocampus and cortex. Some molecules responsible for dysfunction in insulin signaling are GSK-3β, Akt, PI3K, and IRS. Irregularities in insulin signaling or insulin resistance may arise from changes in the phosphorylation levels of key molecules, which can be influenced by both stimulation and inactivity. This, in turn, is believed to be a crucial factor contributing to the development of AD, which is characterized by oxidative stress, neuroinflammation, and other pathological hallmarks. Furthermore, this route is known to be indirectly influenced by Nrf2, NF-κB, and the caspases. This mini-review delves into the intricate relationship between insulin signaling and AD, exploring how disruptions in this pathway contribute to disease progression. Moreover, we examine recent advances in drug delivery systems designed to target insulin signaling for AD treatment. From oral insulin delivery to innovative nanoparticle approaches and intranasal administration, these strategies hold promise in mitigating the impact of insulin resistance on AD. This review consolidates current knowledge to shed light on the potential of these interventions as targeted therapeutic options for AD.

Keywords: Alzheimer’s disease, amyloid-beta plaques, antidiabetics, drug delivery systems, insulin signaling, intranasal drug delivery, metformin, nanoparticles, neurodegeneration, tau phosphorylation

DOI: 10.3233/JAD-231181

Journal: Journal of Alzheimer's Disease, vol. 98, no. 4, pp. 1169-1179, 2024