Leptin‐based hexamers facilitate memory and prevent amyloid‐driven AMPA receptor internalisation and neuronal degeneration

Abstract

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Leptin prevents aberrant targeting of tau to hippocampal synapses via PI 3 kinase driven inhibition of GSK3β

“…In conclusion, it is well established that leptin has potent neuroprotective properties against the aberrant effects of Aβ (Doherty et al, 2013, 2022; Magalhães et al, 2015; Malekizadeh et al, 2017; McGregor & Harvey, 2018). Recent studies have highlighted the pivotal role of tau in mediating Aβ‐induced toxicity and have also identified the crucial role tau plays in AD‐related synaptic dysfunction.…”

“…Previous studies have shown that movement of tau to synapses results in AMPAR removal from hippocampal synapses (Miller et al, 2014; Teravskis et al, 2021). To verify if Aβ 1‐42 promotes removal of synaptic AMPARs, immunocytochemical approaches were used to monitor the cell surface expression of the AMPA receptor subunit, GluA1 (Doherty et al, 2022; Moult et al, 2010). Incubation with Aβ 1‐42 , (1 μM, 1 h) had no effect on GluA1 surface expression per se as surface GluA1 immunolabelling was not significantly different to control (0.90 ± 0.02; n = 48 dendrites; n = 4 cultures; F [7376] = 13.4; p = 0.14; Figure 5a,b).…”

“…Previous studies have shown that movement of tau to synapses results in AMPAR removal from hippocampal synapses (Miller et al, 2014;Teravskis et al, 2021). To verify if Aβ 1-42 promotes removal of synaptic AMPARs, immunocytochemical approaches were used to monitor the cell surface expression of the AMPA receptor subunit, GluA1 (Doherty et al, 2022;Moult et al, 2010) cultures; F [6329] = 8.9; p = 1.00; Figure 5e). However, TCS2002 mimicked the effects of leptin, as % co-localisation of GluA1 and PSD-95 was not significantly different from control, in TCS2002 plus Aβ 1-42 treated neurons (53.77 ± 1.15% co-localisation; n = 48 dendrites; n = 4 cultures; F [6329] = 8.9; p = 1.00; Figure 5e).…”

“…However, leptin also possesses cognitive‐enhancing properties, attributed to its hippocampal actions (Irving & Harvey, 2021). Thus, leptin enhances performance in hippocampal‐dependent memory tasks (Doherty et al, 2022; Malekizadeh et al, 2017; Oomura et al, 2006), whereas leptin‐insensitive animals ( fa/fa rats, db/db mice) display impaired memory (Li et al, 2002). Additionally, leptin regulates the cellular events underlying learning and memory, as it enhances long‐term potentiation (LTP; Shanley et al, 2001; Wayner et al, 2004), and alters excitatory synaptic strength at hippocampal Schaffer‐collateral (SC)‐CA1 and temporoammonic (TA)‐CA1 synapses by regulating α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptor (AMPAR) trafficking (Luo et al, 2015; McGregor et al, 2018; Moult et al, 2010).…”

“…Acute exposure to Aβ also promotes AMPAR internalisation and facilitates the induction of long-term depression (LTD; Shankar et al, 2008;Li et al, 2009), whereas chronic Aβ treatment leads to neuronal cell death (Martins et al, 2013). Recent evidence indicates that leptin protects against these aberrant effects of Aβ on synaptic function and neuronal viability (Doherty et al, 2013(Doherty et al, , 2022Malekizadeh et al, 2017), as well as reducing Aβ production and burden (Fewlass et al, 2004;Marwarha et al, 2010).…”