Leptin reduces Alzheimer’s disease-related tau phosphorylation in neuronal cells

Abstract

Leptin is a centrally-acting hormone controlling metabolic pathways. Recently, it was shown that leptin can reduce amyloid β levels both in vitro and in vivo. Herein, phosphorylation of tau was investigated following treatment of neuronal cells with leptin and insulin. Specifically, phosphorylation of tau at aa residues Ser 202 , Ser 396 and Ser 404 were monitored in retinoic-acid induced, human cell-lines: SH-SY5Y and NTera-2. Both hormones induced concentration-and timedependent reductions of tau phosphoylation, and were synergestic at suboptimum concentrations. Importantly, leptin was 300-fold more potent than insulin (IC 50 L= 46.9 nM vs IC 50 I= 13.8 µM). A central role for AMP-dependent kinase as a mediator of leptin's action is demonstrated by the ability of 5-Aminoimidazole-4-carboxyamide ribonucleoside (AICAR) to decrease tau phosphorylation and, by blocking leptin in the presence of Compound C. Thus, leptin, which ameliorates both, amyloid β and tau-related pathological pathways, holds promise as a novel therapeutic for Alzheimer's disease.

Inflammation, Defective Insulin Signaling, and Mitochondrial Dysfunction as Common Molecular Denominators Connecting Type 2 Diabetes to Alzheimer Disease

“…Initially described for its role in satiety and long-term body weight maintenance, leptin was recently proposed to regulate cognition, axonal growth, and synaptogenesis in extrahypothalamic regions (112). Moreover, leptin induces hippocampal neurogenesis (113), reduces Ab generation in vitro (114), and improves cognitive performance (114) in transgenic mouse models of AD. Lower plasma levels of leptin have further been associated with increased risk of development of AD (115).…”

Neuroprotective and anti-ageing role of leptin

“…AD has been well characterized as a multifactorial neurodegenerative process characterized by progressive neuronal loss, gliosis and accumulation of two markers of disease: senile plaques (aggregates of b-amyloid peptides) and neurofibrillary tangles (hyperphosphorylated tau protein) (Greco et al 2008(Greco et al , 2009a. The formation of b-amyloid aggregates is the result of an abnormal amyloid precursor protein cleavage by b-and g-secretases.…”

“…Published data suggest that Lep regulates tau phosphorylation through a pathway involving both AMPK and GSK3b, leading the enzyme to this inactive form by the activation of serine-9 phosphorylation (Greco et al 2008(Greco et al , 2009a. Thus, Lep, which ameliorates both amyloid b-and t-related pathological pathways, holds promise as a therapeutic for AD (Fig.…”

“…Intervention in one or more of these factors could slow or limit the process of amyloidogenesis. In the context of the b-amyloid hypothesis for AD, Lep may interfere with the pathogenesis of AD in different ways by a) inhibiting the amyloidogenic process (Greco et al 2008); b) decreasing the activity of glycogen synthase kinase-3b (GSK3b) and, thus, reducing the levels of tau protein phosphorylation (Greco et al 2009b) and c) improving the cognitive function (Tezapsidis et al 2009). …”

Clinicotherapeutic Potential of Leptin in Alzheimer’s Disease and Parkinson’s Disease

“…Leptin prevents neuronal death by reducing A levels both in vitro and in vivo, as well as by reducing tau hyperphosphorylation [40,41]. The neuroprotective role of leptin has been extensively studied in both in vitro and in vivo models of neurodegeneration [42][43][44].…”