Alzheimer's Disease: An Update and Insights Into Pathophysiology

Murtala Bello Abubakar; Kamaldeen Olalekan Sanusi; Azizah Ugusman; Wael Mohamed; Haziq Kamal; Nurul Husna Ibrahim; Ching Soong Khoo; Jaya Kumar

doi:10.3389/fnagi.2022.742408

Alzheimer's Disease: An Update and Insights Into Pathophysiology

Front Aging Neurosci. 2022 Mar 30:14:742408. doi: 10.3389/fnagi.2022.742408. eCollection 2022.

Authors

Murtala Bello Abubakar^{1

2}, Kamaldeen Olalekan Sanusi^{1

2}, Azizah Ugusman³, Wael Mohamed^{4

5}, Haziq Kamal³, Nurul Husna Ibrahim³, Ching Soong Khoo⁶, Jaya Kumar³

Affiliations

¹ Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, Usmanu Danfodiyo University, Sokoto, Nigeria.
² Centre for Advanced Medical Research and Training, Usmanu Danfodiyo University, Sokoto, Nigeria.
³ Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.
⁴ Department of Basic Medical Science, Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan, Malaysia.
⁵ Department of Clinical Pharmacology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt.
⁶ Neurology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia.

Abstract

Alzheimer's disease (AD) is an irreversible brain disorder associated with slow, progressive loss of brain functions mostly in older people. The disease processes start years before the symptoms are manifested at which point most therapies may not be as effective. In the hippocampus, the key proteins involved in the JAK2/STAT3 signaling pathway, such as p-JAK2-Tyr1007 and p-STAT3-Tyr705 were found to be elevated in various models of AD. In addition to neurons, glial cells such as astrocytes also play a crucial role in the progression of AD. Without having a significant effect on tau and amyloid pathologies, the JAK2/STAT3 pathway in reactive astrocytes exhibits a behavioral impact in the experimental models of AD. Cholinergic atrophy in AD has been traced to a trophic failure in the NGF metabolic pathway, which is essential for the survival and maintenance of basal forebrain cholinergic neurons (BFCN). In AD, there is an alteration in the conversion of the proNGF to mature NGF (mNGF), in addition to an increase in degradation of the biologically active mNGF. Thus, the application of exogenous mNGF in experimental studies was shown to improve the recovery of atrophic BFCN. Furthermore, it is now coming to light that the FGF7/FGFR2/PI3K/Akt signaling pathway mediated by microRNA-107 is also involved in AD pathogenesis. Vascular dysfunction has long been associated with cognitive decline and increased risk of AD. Vascular risk factors are associated with higher tau and cerebral beta-amyloid (Aβ) burden, while synergistically acting with Aβ to induce cognitive decline. The apolipoprotein E4 polymorphism is not just one of the vascular risk factors, but also the most prevalent genetic risk factor of AD. More recently, the research focus on AD shifted toward metabolisms of various neurotransmitters, major and minor nutrients, thus giving rise to metabolomics, the most important "omics" tool for the diagnosis and prognosis of neurodegenerative diseases based on an individual's metabolome. This review will therefore proffer a better understanding of novel signaling pathways associated with neural and glial mechanisms involved in AD, elaborate potential links between vascular dysfunction and AD, and recent developments in "omics"-based biomarkers in AD.

Keywords: Alzheimer; JAK; NGF; dementia; diagnose; omic; therapeutic; vascular.

Publication types

Review