AD is a progressive and disabling neurodegenerative disease that is common in the elderly population, severely damaging their physical and mental health. The onset of AD typically occurs after the age of 65, with global prevalence reaching approximately 35.6 million cases in 2010. With worldwide populations aging, it is predicted that more than 65.7 million people will have AD by 2030, and more than 100 million by 2050. Currently, available treatments for AD primarily focus on alleviating the progression of the disease, with no effective therapies capable of reversing its course or significantly enhancing treatment outcomes. The pathogenesis of AD is not fully understood, but key pathological features include the excessive aggregation of amyloid-β protein (Aβ), abnormal phosphorylation of Tau protein leading to neurofibrillary tangles, neuronal loss, and inflammation resulting from activated glial cells. Recent advancements in the understanding of cellular signaling pathways have gradually unveiled several mechanisms contributing to AD, with notable pathways including PI3K/Akt, Wnt/β-catenin, MAPK, and JAK2/STAT3. Components within these signaling pathways hold potential as therapeutic targets and avenues for future treatment strategies.
The PI3K/Akt signaling axis is closely related to critical cellular mechanisms including cell survival, metabolism, and apoptosis. The recruitment of PI3K is primarily initiated by the activation of receptor tyrosine kinases (RTKs), which subsequently catalyze the conversion of PIP2 into PIP3. As a second messenger, PIP3 activates downstream signaling through protein kinase B (PKB/Akt), which translocates to the cell membrane to promote pathways associated with cell growth and survival. Phosphorylation of two key residues, Thr 308 and Ser 473, activates kinase AKT, allowing it to regulate downstream proteins including the mammalian target of rapamycin (mTOR), glycogen synthase kinase 3β (GSK-3β), and cAMP response element-binding protein (CREB). mTOR is involved in the release of pro-inflammatory factors, while CREB plays a role in neuronal survival and cognitive functions such as learning and memory. Additionally, GSK-3β is associated with the hyperphosphorylation of tau protein. Research indicates that AKT modulates neuronal survival by directly inhibiting pro-apoptotic transcription factor Forkhead or apoptosis regulator Bad, and indirectly by phosphorylating GSK-3β at Ser9 to suppress its activity. Furthermore, AKT inhibits the primary apoptotic pathway mediated by JNK-p53-Bax, leading to the upregulation of anti-apoptotic factors such as IAP, Bcl-2, and Bcl-xl.
Increasing evidence suggests that the downregulation of Wnt/β-catenin signaling in the aging brain may lead to decreased neurogenesis and cognitive impairments. The Wnt ligands bind with Frizzled (Fzd) receptors and low-density lipoprotein receptor 5/6 (LRP 5/6), which facilitates the recruitment of Disheveled (Dvl) proteins and Axin at the cell membrane, ultimately resulting in the stabilization of β-catenin and the inhibition of GSK3β. Subsequent nuclear translocation of β-catenin allows it to interact with T cell-specific transcription factors (TCF)/lymphoid enhancer factors (LEF) and other cofactors, thereby regulating the transcription of Wnt target genes. In the aging brain, there is a noted downregulation of Wnt proteins and Dvl, along with dysregulation and loss of function of the Wnt co-receptor LRP6, and an upregulation of the Wnt antagonist DKK1, all contributing to the suppression of Wnt/β-catenin signaling. This downregulation activates GSK3β, leading to hyperphosphorylation of tau, accumulation of Aβ, microglia-mediated inflammatory responses, and memory deficits. Several therapeutic agents targeting the Wnt/β-catenin pathway may be beneficial for Alzheimer's disease, such as DKK1 inhibitors, Wnt activators, and statins. These agents aim to restore Wnt/β-catenin signaling, thereby exerting their therapeutic effects.
In mammalian cells, mitogen-activated protein kinases (MAPKs) primarily include p38 MAPK, ERK 1/2, JNK, and ERK 5/BMK-1. These MAPKs play a crucial role in transmitting extracellular signals to the intracellular environment through a phosphorylation cascade that involves three key kinases: MAPK, MAPKK, and MAPKKK. Within the central nervous system (CNS), the activation of p38 MAPK is associated with various pathological events such as hyperphosphorylation of Tau, production, and accumulation of reactive oxygen species (ROS), the release of pro-inflammatory factors, reduction in dendritic spine density, memory impairments, and neuronal apoptosis. Conversely, ERK activation is linked to neuronal survival, while JNK activation correlates with the generation and deposition of Aβ, Tau hyperphosphorylation, and neuroinflammation. Numerous in vitro studies have demonstrated that inhibiting the MAPK signaling pathway can effectively suppress neuroinflammation in BV2 microglia cells.
The JAK2/STAT3 signaling pathway plays a crucial role in AD by regulating inflammatory responses that influence disease progression. When stimulated by endotoxins (LPS), interferon-gamma (IFN-γ), and other cytokines, the JAK2/STAT3 pathway is activated. The resulting phosphorylated STAT3 protein forms dimers that translocate to the nucleus, where they bind to target genes and modulate the transcription of various pro-inflammatory genes. This leads to an excessive accumulation of inflammatory mediators and subsequent inflammation. Therefore, inhibiting this pathway may represent a potential therapeutic strategy for mitigating neuroinflammatory damage in AD.
AD has emerged as a significant global public health challenge. Early detection and intervention in the disease's progression can reduce treatment costs and delay its advancement. Consequently, the utilization of informative biomarkers is crucial for providing accurate diagnoses in the early stages of the disease. Common biomarkers associated with AD include:
The pathogenesis of AD involves a complex interplay of various biological pathways, presenting new opportunities for targeted therapeutic approaches. By elucidating potential targets and novel drugs within the PI3K/Akt, Wnt/β-catenin, MAPK, and JAK2/STAT3 signaling pathways, we aspire to advance research efforts aimed at combating AD.
Several candidate drugs targeting the PI3K/Akt signaling axis have been identified for the treatment and improvement of AD. Leptin, recognized as a cognitive enhancer, activates the p-Akt signaling pathway, aiding in the recovery of lost neurons and reducing apoptosis, thereby improving spatial learning deficits and suppressing pro-inflammatory cytokine expression. Lithium, another natural compound with therapeutic potential for AD, interacts with brain-derived neurotrophic factor (BDNF) to stimulate Akt, which inhibits GSK-3β-mediated apoptosis. Several clinical trials have investigated the neuroprotective effects of lithium on AD patients. Additionally, dual PI3K/mTOR inhibitors such as PI103, dactolisib, voxtalisib, and SF1126 show promise by simultaneously inhibiting PI3K and mTORC1/mTORC2. ARA0114418, a selective ATP-competitive GSK-3β inhibitor, demonstrates efficacy by preventing tau protein hyperphosphorylation in vitro and in vivo. Other GSK-3β inhibitors, including TDZD-8, AZD1080, and palinurin 7, have also proven effective in AD research.
Targeted therapies for AD involving the Wnt/β-catenin signaling pathway include gallocyanine, WASP-1, and statins. Gallocyanine, a DKK1 inhibitor, is known to reverse DKK1-mediated suppression of Wnt/β-catenin signaling, thereby reducing tau phosphorylation. WASP-1, a small-molecule Wnt activator, has demonstrated the potential to improve synaptic dysfunction and memory deficits in AD mouse models. Statins have been shown to activate Wnt/β-catenin signaling, inhibiting Aβ-induced neuronal apoptosis. Numerous studies suggest that statin use may help prevent AD pathology.
Drugs targeting the AMPK signaling pathway in AD can achieve therapeutic effects by inhibiting this pathway. Currently, several drugs targeting the MAPK signaling pathway in AD include MW181, VX-745, MMI-0100, selumetinib, etc. MW181, a selective p38α MAPK inhibitor, effectively penetrates the blood-brain barrier (BBB), reducing tau phosphorylation and the production of pro-inflammatory cytokines in brain tissue. VX-745, another small-molecule p38α MAPK inhibitor, has been shown in preclinical studies to lower IL-1β levels in the hippocampus of aged rats, demonstrating its anti-neuroinflammatory effects. Targeting MAPK-activated protein kinase II (MK2), MMI-0100 is a cell-penetrating peptide inhibitor that dramatically lowers pro-inflammatory cytokine output in mice by preventing MK2 phosphorylation and LPS-induced microglial activation. Additionally, Selumetinib, a selective non-ATP competitive MEK1/2 inhibitor, can effectively suppresses ERK1/2 phosphorylation.
Regarding drugs targeting the JAK2/STAT3 signaling pathway in AD, some examples are (E)-2-methoxy-4-(3-(4-methoxyphenyl) prop-1-en-1-yl) phenol (MMPP), stattic, astaxanthin (AXT), etc. Both in vitro and in vivo investigations have demonstrated that MMPP inhibits the DNA binding activity of STAT3 activation, hence lowering LPS-induced neuroinflammation and memory impairment. Stattic acts as a selective STAT3 inhibitor, effectively preventing neuroinflammation and abnormal regulation of BACE1, making it a promising candidate for AD therapy. AXT is a ketone-type carotenoid with neuroprotective effects. Studies have shown that AXT reduces the expression of LPS-induced inflammatory proteins through directly combining with the DNA-binding and linkage structural domains of STAT3, thereby causing anti-neuroinflammatory effects and suppressing APP generation.
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