Therapeutic Approaches to Alzheimer’s Type of Dementia: A Focus on FGF21 Mediated Neuroprotection

Abstract

Neurodegenerative disorders are the most devastating disorder of the nervous system. The pathological basis of neurodegeneration is linked with dysfunctional protein trafficking, mitochondrial stress, environmental factors and aging. With the identification of insulin and insulin receptors in some parts of the brain, it has become evident that certain metabolic conditions associated with insulin dysfunction like Type 2 diabetes mellitus (T2DM), dyslipidemia, obesity etc., are also known to contribute to neurodegeneration mainly Alzheimer’s Disease (AD). Recently, a member of the fibroblast growth factor (FGF) superfamily, FGF21 has proved tremendous efficacy in diseases like diabetes mellitus, obesity and insulin resistance (IR). Increased levels of FGF21 have been reported to exert multiple beneficial effects in metabolic syndrome. FGF21 receptors are present in certain areas of the brain involved in learning and memory. However, despite extensive research, its function as a neuroprotectant in AD remains elusive. FGF21 is a circulating endocrine hormone which is mainly secreted by the liver primarily in fasting conditions. FGF21 exerts its effects after binding to FGFR1 and co-receptor, β-klotho (KLB). It is involved in regulating energy via glucose and lipid metabolism. It is believed that aberrant FGF21 signalling might account for various anomalies like neurodegeneration, cancer, metabolic dysfunction etc. Hence, this review will majorly focus on FGF21 role as a neuroprotectant and potential metabolic regulator. Moreover, we will also review its potential as an emerging candidate for combating metabolic stress induced neurodegenerative abnormalities.

Genetic Evidence Supporting Fibroblast Growth Factor 21 Signalling as a Pharmacological Target for Cardiometabolic Outcomes and Alzheimer’s Disease

“…In rodents and non-human primates, FGF21 treatment has beneficial effects on cardiometabolic outcomes, such as reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, and cardiovascular diseases [ 7 ]. Furthermore, FGF21 has been implicated in protecting against Alzheimer’s disease [ 8 ], as well as improving lifespan [ 9 ]. However, studies investigating the association between circulating FGF21 and these clinical outcomes in humans have been inconclusive [ 7 , 10 ].…”

Disease-specific plasma levels of mitokines FGF21, GDF15, and Humanin in type II diabetes and Alzheimer’s disease in comparison with healthy aging

“…Accordingly, FGF21 is in fact considered as a possible therapeutic approach for metabolic disorders such as T2D [ 18 , 19 ]. Other studies also suggest a neuroprotective role against pathologies such as AD [ 20 , 21 ].…”

Alignment of Alzheimer's disease amyloid β‑peptide and klotho

“…FGF21 regulates energy consumption by influencing glucose and lipid metabolism. Deranged FGF21 signaling might account for some forms of neurodegeneration, and FGF21 could be therapeutic in AD ( 20 ). Structurally, FGF21 is a 181 amino acid peptide (~22.3 kDa molecular mass) derived from a 209 amino acid mature protein encoded by the FGF21 gene located on chromosome 19.…”