Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative disorder characterized by the accumulation of amyloid plaques and neurofibrillary tangles. Interestingly, individuals with metabolic syndromes share some pathologies with those diagnosed with AD including neuroinflammation, insulin resistance and cognitive deficits. Leptin, an adipocyte-derived hormone, regulates metabolism, energy expenditure and satiety via its receptor, LepR. To investigate the possible involvement of leptin in AD, we examined the distribution of leptin and LepR in the brains of the 5XFAD mouse model of AD, utilizing immunofluorescent staining in young (10–12-weeks; n = 6) and old (48–52-weeks; n = 6) transgenic (Tg) mice, together with age-matched wild-type (WT) controls for both age groups (young-WT, n = 6; old-WT, n = 6). We also used double immunofluorescent staining to examine the distribution of leptin and leptin receptor expression in astrocytes. In young 5XFAD, young-WT and old-WT mice, we observed neuronal and endothelial expression of leptin and LepR throughout the brain. However, neuronal leptin and LepR expression in the old 5XFAD brain was significantly diminished. Reduced neuronal leptin and LepR expression was accompanied by plaque loading and neuroinflammation in the AD brain. A marked increase in astrocytic leptin and LepR was also observed in old 5XFAD mice compared to younger 5XFAD mice. We postulate that astrocytes may utilize LepR signalling to mediate and drive their metabolically active state when degrading amyloid in the AD brain. Overall, these findings provide evidence of impaired leptin and LepR signalling in the AD brain, supporting clinical and epidemiological studies performed in AD patients.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain that is characterized by memory impairment and cognitive dysfunction [1,2]
AD has been reported as a multifactorial disease with multiple epidemiological and clinical studies reporting that patients with metabolic syndromes including type 2 diabetes mellitus (T2DM) and/or obesity are at increased risk of developing AD [8,9,10,11]
We observed a qualitative decrease in expression of both leptin and leptin and its receptor (LepR) in the old-WT and old-Tg mice compared with the younger WT and Tg mice
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disease of the brain that is characterized by memory impairment and cognitive dysfunction [1,2]. Pathological hallmarks of AD are the deposition of amyloid beta (Aβ) plaques and neurofibrillary tangles [3,4]. The accumulation of these proteinaceous deposits induce synaptic dysfunction, neuroinflammation and oxidative damage, resulting in neurodegeneration [5]. A study discovered an increased amyloid precursor protein (APP) load, in addition to a decreased insulin receptor activity in the brain of diabetes-induced (via intraperitoneal administration of streptozotocin) AD-transgenic hAPP (human-APP) mice [16]. Another study investigating the behavioural responses of transgenic T2DM and AD mice, reported that both strains elicited similar learning and memory impairments, as well as increased anxiety and fear responses [12]. The authors noted increased insulin resistance and impaired insulin signalling caused by Aβ cytotoxicity [18]
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