Therapeutic Potential of AMP-Activated Protein Kinase in Alzheimer’s Disease

Abstract

Currently there is no cure or effective disease-modifying therapy for Alzheimer’s disease (AD), the most common form of dementia that is becoming a global threat to public health. It is important to develop novel therapeutic strategies targeting AD pathophysiology particularly synaptic failure and cognitive impairments. Recent studies revealed several molecular signaling pathways potentially linked to brain pathology and synaptic failure in AD, including AMP-activated protein kinase (AMPK), a master kinase that plays a central role in the maintenance of cellular energy homeostasis. Particularly, hyperactive AMPK via phosphorylation has been linked to AD-associated synaptic plasticity impairments, indicating suppression of AMPK activity might be beneficial for cognitive deficiency in AD. In this review, we will discuss how targeting dysregulation of AMPK signaling could be a feasible therapeutic approach for AD.

Brain-specific repression of AMPKα1 alleviates pathophysiology in Alzheimer’s model mice

“…As a master kinase functioning to maintain energy homeostasis, AMPK plays a key role in many biological processes. Considering all the downstream effectors of AMPK, dysregulation of AMPK signaling may be connected to many, if not all, cellular abnormalities and functional impairments in AD (5).…”

“…Multiple studies indicate a role of AMPK in AD-associated Aβ and tau pathology (5,6,53,54). AMPK regulation may affect AD brain pathology, although controversy arises regarding whether Aβ accumulation and tau hyperphosphorylation can be alleviated or aggravated by the activation of AMPK (5,6,53,54). On the other hand, increased AMPK activity (assessed by AMPKα phosphorylation) was observed in brain tissue from AD patients and Tg mouse jci.org Volume 130 Number 7 July 2020 jci.org Volume 130 Number 7 July 2020 mRNA translation (14).…”

“…There is an urgent need to understand the molecular mechanisms underlying AD pathophysiology and accordingly to identify novel therapeutic targets for this devastating neurodegenerative disease. Emerging evidence points to a role of AMPK in AD pathophysiology (3)(4)(5)(6). AMPK is a Ser/Thr kinase that functions as a central energy sensor at the molecular level.…”

The Bewildering Effect of AMPK Activators in Alzheimer’s Disease: Review of the Current Evidence

“…is in turn explains the downstream alterations such as tangle formation, Aβ plaque formation, alterations in metabolic signaling and memory impairment, and inflammatory and apoptotic events [41]. Figure 1 summarizes the various effects of AMPK which impact the pathogenesis of AD (see Figure 1) [42]. In the succeeding portions, we review the effect of AMPK activation in AD with regard to its effect on amyloid-β aggregation, tau phosphorylation, and oxidative stress.…”

scGRNom: a computational pipeline of integrative multi-omics analyses for predicting cell-type disease genes and regulatory networks

“…Specifically, in AD, multiple pathways implicated in neurodegradation and intercellular signaling were found to be significantly enriched across multiple cell types. For instance, AMPK signaling (p_excitatory<9.65e-7, p_oligodendrocytes<2.98e-10) [57,58], asymmetric and dopaminergic synapses (p_microglia<2.27e-21, p_oligodencrocytes<2.26e-5, p_excitatory<5.82e-17, p_inhibitory<3.29e-15) [59] and (p_microglia<7.94e-8, p_oligodencrocytes<2.78e-7, p_excitatory<8.07e-7, p_inhibitory<1.37e-7) [60], respectively, as well as postsynaptic specialization (p_microglia<5.88e-21, p_excitatory<1.73e-17, p_inhibitory<1.37e-15) [61] were all found to be significantly enriched in more than two cell types. The AMPK signaling is involved as a master kinase regulation element in ATP synthesis production and in the context of Alzheimer's Disease, has aided both amyloid production and tau phosphorylation [30].…”