Intranasal Paclitaxel Alters Alzheimer's Disease Phenotypic Features in 3xTg-AD Mice.

BACKGROUND: Microtubule stabilizing drugs, commonly used as anti-cancer therapeutics, have been proposed for treatment of Alzheimer's disease (AD); however, many do not cross the blood-brain barrier. OBJECTIVE: This research investigated if paclitaxel (PTX) delivered via the intranasal (IN) route could alter the phenotypic progression of AD in 3xTg-AD mice. METHODS: We administered intranasal PTX in 3XTg-AD mice (3xTg-AD n = 15, 10 weeks and n = 10, 44 weeks, PTX: 0.6 mg/kg or 0.9%saline (SAL)) at 2-week intervals. After treatment, 3XTg-AD mice underwent manganese-enhanced magnetic resonance imaging to measure in vivo axonal transport. In a separate 3XTg-AD cohort, PTX-treated mice were tested in a radial water tread maze at 52 weeks of age after four treatments, and at 72 weeks of age, anxiety was assessed by an elevated-plus maze after 14 total treatments. RESULTS: PTX increased axonal transport rates in treated 3XTg-AD compared to controls (p≤0.003). Further investigation using an in vitro neuron model of Aß-induced axonal transport disruption confirmed PTX prevented axonal transport deficits. Confocal microscopy after treatment found fewer phospho-tau containing neurons (5.25±3.8 versus 8.33±2.5, p < 0.04) in the CA1, altered microglia, and reduced reactive astrocytes. PTX improved performance of 3xTg-AD on the water tread maze compared to controls and not significantly different from WT (Day 5, 143.8±43 versus 91.5±77s and Day 12, 138.3±52 versus 107.7±75s for SAL versus PTX). Elevated plus maze revealed that PTX-treated 3xTg-AD mice spent more time exploring open arms (Open arm 129.1±80 versus 20.9±31s for PTX versus SAL, p≤0.05). CONCLUSION: Taken collectively, these findings indicate that intranasal-administered microtubule-stabilizing drugs may offer a potential therapeutic option for treating AD.

Modulation of insulin signaling rescues BDNF transport defects independent of tau in amyloid-ß oligomer-treated hippocampal neurons.

Defective brain insulin signaling contributes to the cognitive deficits in Alzheimer's disease (AD). Amyloid-beta oligomers (AßOs), the primary neurotoxin implicated in AD, downregulate insulin signaling by impairing protein kinase B/AKT, thereby overactivating glycogen synthase kinase-3ß. By this mechanism, AßOs may also impair axonal transport before tau-induced cytoskeletal collapse and cell death. Here, we demonstrate that a constitutively active form of protein kinase B/AKT prevents brain-derived neurotrophic factor (BDNF) transport defects in AßO-treated primary neurons from wild type (tau(+/+)) and tau knockout (tau(-/-)) mice. Remarkably, inhibition of glycogen synthase kinase-3ß rescues BDNF transport defects independent of tau. Furthermore, exendin-4, an anti-diabetes agent, restores normal BDNF axonal transport by stimulating the glucagon-like peptide-1 receptor to activate the insulin pathway. Collectively, our findings indicate that normalized insulin signaling can both prevent and reverse BDNF transport defects in AßO-treated neurons. Ultimately, this work may reveal novel therapeutic targets that regulate BDNF trafficking, promote its secretion and uptake, and prolong neuronal survival during AD progression.