Alzheimer’s disease (AD) is the most common cause of dementia syndrome in the elderly and a devastating neurodegenerative disease without effective therapies available currently (Association, 2023, Holtzman et al., 2012, Querfurth and LaFerla, 2010, Roberson and Mucke, 2006). AD is a multifactorial disease characterized by distinct brain pathology including amyloid plaques and neurofibrillary tangles. Meanwhile, mounting evidence suggests that synaptic dysfunction plays a critical role in AD pathogenesis, leading to the hypothesis that AD is a disease of “synaptic failure” (Ma and Klann, 2012, Masliah, 1995, Selkoe, 2002). Understanding the molecular signaling mechanisms underlying synaptic failure in AD could thus provide insights into identification of novel therapeutic targets and diagnostic/prognostic biomarkers (Teich et al., 2015).

Synaptic plasticity is defined as the activity-dependent modification (strengthened or weakened) at preexisting synapses and established as the primary cellular model for learning and memory (Cooke and Bliss, 2006, Neves et al., 2008). There are two prototypic forms of synaptic plasticity: long-term potentiation (LTP) and long-term depression (LTD), both are considered to mediate the cellular process of learning and memory, and are impaired in various rodent models of AD (Li et al., 2009, Ma et al., 2014, Malenka and Bear, 2004, Valdivia et al., 2023, Zimmermann et al., 2020). Compared to investigation of LTP regulation in AD, much fewer studies are reported on AD-related LTD dysregulation and associated molecular signaling mechanisms. One established form of LTD is metabotropic glutamate receptor-dependent LTD (mGluR-LTD), which is usually induced experimentally by selective group 1 mGluR agonists such as DHPG [(RS)-3,5-dihydroxyphenylglycine] (Lüscher and Huber, 2010, Yang et al., 2016a). Dysregulation of mGluR-LTD has been linked to cognitive syndromes associated with various neurological disorders including Fragile X syndrome and AD (Bhattacharya et al., 2012, Huber et al., 2002, Lüscher and Huber, 2010, Valdivia et al., 2023, Yang et al., 2021a). Previous studies also suggest that mGluR might be a potential receptor/co-receptor for amyloid beta (Aβ), the main components of the AD-associated brain pathological plaques (Hu et al., 2014, Um et al., 2013). Besides mGluR-LTD, another established form of LTD is NMDA receptor (NMDAR)-dependent LTD, which is often induced by various protocols of low-frequency stimulation (LFS), as compared to the high-frequency stimulation (HFS) protocol to induce NMDAR-dependent LTP (Malenka and Bear, 2004).

AMP-activated protein kinase (AMPK) is a conserved Ser/Thr kinase that plays a critical role in maintaining cellular energy homeostasis, disruption of which has been linked to multiple neurodegenerative diseases including AD (Lin and Beal, 2006, Ma et al., 2014, Ryu et al., 2019, Zimmermann et al., 2020). Mammalian AMPK consists of catalytic α subunit and regulatory β and γ subunits. The AMPKα subunit has two isoforms (AMPKα1 and AMPKα2), which are encoded by PRKAA1 and PRKAA2 genes that are in chromosome 5 and 1, respectively (Hardie et al., 2012, Steinberg and Hardie, 2023, Steinberg and Kemp, 2009). Our recent studies in mice show isoform-specific roles of AMPKα subunit in regulation of synaptic and cognitive function (Wang et al., 2020, Yang et al., 2021b). Abnormal elevated activities of AMPK, as measured by phosphorylation levels of AMPKα at the Thr172 site, have been observed in brain tissue from AD patients (postmortem) and AD model mice (Ma et al., 2014, Mairet-Coello et al., 2013, Vingtdeux et al., 2011). Furthermore, we have demonstrated that cognitive deficits in aged AD mouse models can be alleviated by genetic suppression of neuronal AMPKα1, but not AMPKα2 (Zimmermann et al., 2020).

Here, taking advantage of the unique mouse models recently generated in our lab, we studied how neuronal inhibition of AMPKα isoforms can affect LTD (both mGluR-LTD and NMDAR-LTD) performance in a mouse model of AD.