Reducing PDK1/Akt Activity: An Effective Therapeutic Target in the Treatment of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a common age-related neurodegenerative disease that leads to memory loss and cognitive function damage due to intracerebral neurofibrillary tangles (NFTs) and amyloid-β (Aβ) protein deposition. The phosphoinositide-dependent protein kinase (PDK1)/protein kinase B (Akt) signaling pathway plays a significant role in neuronal differentiation, synaptic plasticity, neuronal survival, and neurotransmission via the axon–dendrite axis. The phosphorylation of PDK1 and Akt rises in the brain, resulting in phosphorylation of the TNF-α-converting enzyme (TACE) at its cytoplasmic tail (the C-terminal end), changing its internalization as well as its trafficking. The current review aimed to explain the mechanisms of the PDK1/Akt/TACE signaling axis that exerts its modulatory effect on AD physiopathology. We provide an overview of the neuropathological features, genetics, Aβ aggregation, Tau protein hyperphosphorylation, neuroinflammation, and aging in the AD brain. Additionally, we summarized the phosphoinositide 3-kinase (PI3K)/PDK1/Akt pathway-related features and its molecular mechanism that is dependent on TACE in the pathogenesis of AD. This study reviewed the relationship between the PDK1/Akt signaling pathway and AD, and discussed the role of PDK1/Akt in resisting neuronal toxicity by suppressing TACE expression in the cell membrane. This work also provides a perspective for developing new therapeutics targeting PDK1/Akt and TACE for the treatment of AD.

Identification and Validation of Novel Biomarkers for Alzheimer's Disease Based on Akt and Wnt Signaling Pathways

“…In addition to clear Aβ by inducing autophagy, the Protein kinase B (Akt) signaling pathway also causes abnormalities in central insulin signaling and NTFs [21,22]. Glucose transporter 4 (GLUT4) is transported to the neuron membrane under the induction of Akt, which improves insulin transport to brain neurons in learning and memory state [23].…”

Potential Mechanism of Qinggong Shoutao Pill Alleviates Age-associated Memory Decline in D-Galactose-Injured Mice Based on Network Pharmacology, Molecular Docking, and Experimental Verification Integration Strategy

“…mGluR5 supports long-term changes in synaptic strength by regulating the transcription and translation of essential synaptic proteins [49]. Other identi ed core targets AKT1, EGFR, MAPK1 and CNR1 (CB1) have been approved to take part in enhancing learning and memory performance through regulation [50][51][52][53].…”

ADME profiling, molecular docking, DFT, and MEP analysis reveal cissamaline, cissamanine, and cissamdine from Cissampelos capensis L.f. as potential anti-Alzheimer's agents

“…85 Studies have revealed that TACE has been associated with inammatory diseases, such as Alzheimer's disease, as increased plasma TACE activity has been observed in subjects with mild cognitive impairment. [86][87][88][89] Inhibition of TACE has the potential to mitigate TNFa levels and amyloid b deposition in Alzheimer's disease, 90 while elevated cerebrospinal uid (CSF) levels of TACE activity and soluble TNF receptors have been observed in patients with Alzheimer's disease. 87 TACE is a multidomain metalloproteinase that processes tumor necrosis factor and a host of other proteins.…”