Ecological and social factors lead to variation in parental care between sexes in a burying beetle.

Alzheimer’s disease (AD) is a neurological disorder that impairs neurocognitive function. The main pathological features found in AD are the presence of amyloid β (Aβ) plaques and tau neurofibrillary tangles in the brain, resulting in neuronal loss and brain atrophy []. The presence of Aβ plaque is considered the primary pathological condition of AD. It has been reported that the mechanistic target of rapamycin (mTOR) activity is closely related to Aβ deposition and clearance []. Under normal circumstances, the brain rapidly clears insoluble Aβ. However, for patients suffering from AD, the imbalance between the production and clearance of Aβ in the brain causes an increased accumulation of Aβ []. For these patients, mTOR is abnormally activated, resulting in the inhibition of Aβ clearance. Therefore, inhibiting mTOR promotes the Aβ clearance. Inversely, the accumulation of Aβ is known to alter the function of mTOR, which is directly linked to learning and memory. Although not clearly elucidatedas of yet, it has been believed that inhibiting mTOR increases the expression of sirtunin 1 (SIRT1), a key regulator of α-secretase, which, as a result, inhibits the production of Aβ. Rapamycin (Rapa) is an mTOR inhibitor produced by . Caccamo reported that AD-induced mice (3xTg) fed with Rapa-containing food (2.24 mg/kg) for 10 weeks showed a significant reduction in Aβ immunoreactivity of neurons in the CA1 region of the hippocampus []. Chronic inflammation is another major factor in the progression of AD. Nuclear factor-κB (NF-κB) is a key mediator known for the anti-inflammatory effect of Rapa. Rapa exerts anti-inflammatory effects by down-regulating p65, interleukin (IL)-1β, tumor necrosis factor-α (TNF- α) and other factors associated with NF-κB. IL-6 takes a complex role by stimulating the synthesis of Aβ precursor protein while exerting a neuroprotective effect by activating the phagocytic activity of microglia to degrade Aβ. Although controversial, it has been reported that Rapa upregulates IL-6 expression in astrocytes in a Parkinson’s disease mouse model, showing a neuroprotective effect []. It is evident that Rapa improves AD-induced cognitive dysfunction []. The restoration of mTORC1 activity after Rapa treatment demonstrated a significant effect on cognitive performance []. Rapa is reported to enhance synaptic plasticity, which plays a key role in the development of the nervous system, learning and memory, and cognitive function [–]. Rapa also increases synaptic protein expression by increasing mitochondrial autophagy and preventing cytochrome C-mediated apoptosis []. Rapa is known to exert a major effect on aging in rodents [,]. The NIA’s intervention testing program (ITP) identified Rapa as the compound that extends lifespan in rodents when given orally via the mouse chow (14 ppm) and the effect was noticeable across both males and females. The primary mechanism of extending lifespan appears to be the inhibition of lethal neoplastic disease []. Although Rapa has been proven effective in AD, several questions remain to be addressed []. First, Rapa lacks specific targeted effects and as a result potential side effects may occur. There are a few instances regarding Rapa’s adverse effects associated with oral Rapa monotherapy. The most common side effects at the highest dose tested (20 mg/week for 6–16 weeks) were mouth ulcers, headache, fatigue, and neutropenia []. As per Shi , it was found that the long-term oral use of rapamycin for 2–3 months inhibited mTOR activity and reduced TREM2 expression in microglia of AD mice, reducing the uptake and clearance of Aβ by microglia and aggravating AD-like pathological changes in the brains of 5xFAD AD mice []. The animals received Rapa via daily diet at 143 ppm encapsulated Rapa (14 ppm active Rapa; 2.24 mg/kg, 5 g/day). Additional side effects such as glucose intolerance, diabetes, and immunosuppression resulting from long-term use of Rapa are of concern to AD patients []. In this study, to address the non-targeted effect of Rapa and its side effects owing to the long-term oral use, a low dose (0.2 mg/kg) of Rapa was delivered to AD-induced mice intranasally via brain-targeting polymeric micelles. We hypothesized that brain-targeting polymeric micelles carry Rapa effectively to the brain via nose-to-brain route at the lower dose of Rapa, and brain-targeting polymeric micelles carrying Rapa offer the greater therapeutic efficacy on short-term treatment regimen, thereby reducing systemic side effects. The current AD therapeutics are mainly delivered via oral and parenteral routes. The major drawback of these approaches is poor drug concentration, reduced therapeutic efficacy, and greater side effects of systemic toxicity []. Intranasal “nose-to-brain” drug delivery route has been discovered as an alternative approach that addresses these issues and treats the neurological disorders such as migraine (e.g. Onzetra Xsail) and Parkinson’s disease at greater efficacy