The Implication of Androgens in the Presence of Protein Kinase C to Repair Alzheimer’s Disease-Induced Cognitive Dysfunction

Abstract

Aging, as a major risk factor of memory deficiency, affects neural signaling pathways in hippocampus. In particular, age-dependent androgens deficiency causes cognitive impairments. Several enzymes like protein kinase C (PKC) are involved in memory deficiency. Indeed, PKC regulatory process mediates α-secretase activation to cleave APP in β-amyloid cascade and tau proteins phosphorylation mechanism. Androgens and cortisol regulate PKC signaling pathways, affecting the modulation of receptor for activated C kinase 1. Mitogen-activated protein kinase/ERK signaling pathway depends on CREB activity in hippocampal neurons and is involved in regulatory processes via PKC and androgens. Therefore, testosterone and PKC contribute in the neuronal apoptosis. The present review summarizes the current status of androgens, PKC, and their influence on cognitive learning. Inconsistencies in experimental investigations related to this fundamental correlation are also discussed, with emphasis on the mentioned contributors as the probable potent candidates for learning and memory improvement.

Keywords: Androgens; Cognition; Hippocampus; Protein kinase C; Spatial memory.

Fig 1

Phosphorylation sites identified on PKC isoforms. Phosphorylation sites of each isoform have been presented as a color oval. Purple color, conventional PKCα,  , and  ; bitter lemon color (Ser 319), conventional PKCα novel PKC; pink color, PKC ; gray color, PKC ; green color, PKC ε; yellow color, PKC  ; orange color, atypical PKCs. PS, pseudosubstrate; TM, turn motif; HM, hydrophobic motif; PB1, phosphatidylserine-binding domains; Gln, glutamine

Fig 2

Role of steroids in the cell signaling pathways

Fig. 3

Biosynthesis of HSD and DHEA-S in the body

Fig. 4

CREB signaling pathway. Several signaling pathways, including those involving PKA, PKC, DHT, and DHEA, have been associated with the regulation of de novo protein synthesis in the context of synaptic plasticity, converging on the phosphorylation of CREB at Ser133 residue to repair cognition dysfunction. PKA, protein kinase A; DHT, dehydrotestosterone; DHEA, dhedroepiandrosterone; CRE, cAMP response elements. The following binding DHT and DHEA to their receptors in the cytoplasmic membrane, several enzymes like PKC, PKA and CaMK are activated. On the other hand, the mentioned hormones activates CREB protein directly using phopsphorylation on Ser133. Activated CREB protein passes through the nucleus membrane and is bonded to its receptor to occur the gene expression

Fig. 5

Effect of androgens on induction of non-amyloidogenic pathway of AD. AICD, APP intracellular domain. P stands for phosphorylated protein, and (+) in the image describes the activated effect on the group. Hyperphosphorylated tau containing several phosphate groups attached to the tau protein has been shown. PKC leads to activate the polymerization and depolymerization of MT protein via hyperphosphorylated tau in the normal conditions; therefore, it can help the electron transfer in the nervous systems and create action/potential in the synaptic ends