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Abstract
Alzheimer’s disease (AD) is the most common form of dementia worldwide, being characterized by the deposition of senile plaques, neurofibrillary tangles (enriched in the amyloid beta (Aβ) peptide and hyperphosphorylated tau (p-tau), respectively) and memory loss. Aging, type 2 diabetes (T2D) and female sex (especially after menopause) are risk factors for AD, but their crosslinking mechanisms remain unclear. Most clinical trials targeting AD neuropathology failed and it remains incurable. However, evidence suggests that effective anti-T2D drugs, such as the GLP-1 mimetic and neuroprotector liraglutide, can be also efficient against AD. Thus, we aimed to study the benefits of a peripheral liraglutide treatment in AD female mice. We used blood and brain cortical lysates from 10-month-old 3xTg-AD female mice, treated for 28 days with liraglutide (0.2 mg/kg, once/day) to evaluate parameters affected in AD (e.g., Aβ and p-tau, motor and cognitive function, glucose metabolism, inflammation and oxidative/nitrosative stress). Despite the limited signs of cognitive changes in mature female mice, liraglutide only reduced their cortical Aβ1–42 levels. Liraglutide partially attenuated brain estradiol and GLP-1 and activated PKA levels, oxidative/nitrosative stress and inflammation in these AD female mice. Our results support the earlier use of liraglutide as a potential preventive/therapeutic agent against the accumulation of the first neuropathological features of AD in females.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by the accumulation of senile plaques and neurofibrillary tangles (mainly composed of amyloid beta (Aβ) peptide and hyperphosphorylated tau protein (p-tau), respectively) [1,2]
The key neuropathological hallmarks of AD are the deposition of Aβ and hyperphosphorylated tau that occur early in disease pathology in brain areas such as the hippocampus and cortex, long before its clinical diagnosis that relies mostly on memory loss and, to a lower extent, in a few biomarkers [18,38]
Similar to our previous study in 11-month-old 3xTg-AD male mice [37], here we observed a significant increase in brain Aβ1–42, Aβ1–40 and p-tau(Ser396) levels in 3xTg-AD female mice compared to WT ones
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disorder, neuropathologically characterized by the accumulation of senile plaques and neurofibrillary tangles (mainly composed of amyloid beta (Aβ) peptide and hyperphosphorylated tau protein (p-tau), respectively) [1,2]. The involved mechanisms remain debatable, the hormonal fluctuations affecting women from midlife until advanced ages may render them more vulnerable to brain changes and AD [7,8,9,10]. In this respect, early changes in serum estrogen levels were correlated with cognitive impairment years later in aged women [11], and with cortical and hippocampal senile plaque formation and memory deficits in AD female mice [12,13,14,15,16,17]. This, together with the estimates that 2/3 of AD caregivers are women render them at the epicenter of this epidemic [7,8]
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