Disruption of leptin signalling in a mouse model of Alzheimer’s disease

Abstract

Disruption of leptin signalling has been implicated as playing a role in the development of Alzheimer's disease (AD). Leptin has previously been shown to be affected by amyloid-beta (Aβ)-related signalling; however, pathways that link leptin to the disease pathogenesis have not been determined. To characterize the association between increasing age-dependent Aβ levels with leptin signalling and the vulnerable brain regions in AD, we assessed the mRNA and protein expression profile of leptin and leptin receptor (Ob-Rb) at 9 and 18-month-age in APP/PS1 mice. Immunohistochemical labelling demonstrated that leptin and Ob-Rb proteins were localised to neocortical and hippocampal neurons in APP/PS1 and wildtype (WT) mice. Neuronal leptin and Ob-Rb immunolabelling was more prominent in the neocortex of both groups at 9 month of age, while, at 18 months, labelling was reduced in the hippocampus of APP/PS1 mice relative to WT. Immunoblotting analysis demonstrated decreased hippocampal leptin levels, concomitantly with an increased Ob-Rb levels, in APP/PS1 mice compared with WT controls at 18 month of age. While no leptin mRNA was found in either of the groups analysed, Ob-Rb mRNA was significantly decreased in the hippocampus of APP/PS1 mice at both ages analysed. In addition, a significant decreased protein kinase B (Akt) activity concomitantly with an upregulation of suppressor of cytokine signaling-3 (SOCS3) and protein-tyrosine phosphatase 1B (PTP1B) transcripts was present. Thus, these results collectively indicate alterations of leptin signalling in the hippocampus of APP/PS1 mice, providing novel insights about the pathways that could link aberrant leptin signaling to the pathological changes of AD.

The HDAC6 Inhibitor Trichostatin A Acetylates Microtubules and Protects Axons From Excitotoxin-Induced Degeneration in a Compartmented Culture Model

“…Denatured protein samples (20 μg) were electrophoresed into Bolt ®; 4–12% Bis-Tris gels (Invitrogen), transferred to PVDF membrane (Bio-Rad) and incubated overnight with primary antibodies acetylated tubulin (1:1,000 mouse, Sigma), tyrosinated tubulin (1:1,000 rabbit, Millipore), MAP1B (1:1,000 mouse, AbCam). The corresponding anti-rabbit or anti-mouse horseradish peroxidase conjugated secondary antibody (1:7,000, DAKO) was used as previously described (King et al, 2018 ). GAPDH (1:5,000 mouse, Millipore) was used as a loading control.…”

Neuroprotective actions of leptin facilitated through balancing mitochondrial morphology and improving mitochondrial function

“…N ≥ 200 cells from three independent experiments and *** represents significance at p < .001 studies have revealed that higher serum leptin levels protect against cognitive impairment (Holden et al, 2009;Witte et al, 2016) and are associated with a reduced incidence of AD (Gilbert et al, 2018;Lieb et al, 2009). Expression of Ob-Rb is decreased and leptin signalling (Akt) disrupted in the hippocampus of APP/presenilin 1 mice (King et al, 2018) further implicating leptin signalling in AD pathogenesis.…”

Adipose-Derived Molecules–Untouched Horizons in Alzheimer’s Disease Biology

“…A recent investigation showed that leptin attenuates the hyper-phosphorylation of tau protein. Conversely, the hippocampal tissue and CSF of AD patients revealed a high level of leptin and leptin receptors (King et al, 2018). Leptin has been shown to induce autophagy in neuronal cells (Li et al, 2018), but this has not been demonstrated in relation to AD.…”