Novel therapeutic strategy for neurodegeneration by blocking Aβ seeding mediated aggregation in models of Alzheimer's disease

Abstract

Aβ accumulation plays a central role in the pathogenesis of Alzheimer's disease (AD). Recent studies suggest that process of Aβ nucleated polymerization is essential for Aβ fibril formation, pathology spreading and toxicity. Therefore, targeting this process represent an effective therapeutic strategy to slow or block disease progression. To discover compounds that might interfere with the Aβ seeding capacity, toxicity and pathology spreading, we screened a focused library of FDA-approved drugs in vitro using a seeding polymerization assay and identified small molecule inhibitors that specifically interfered with Aβ seeding-mediated fibril growth and toxicity. Mitoxantrone, bithionol and hexachlorophene were found to be the strongest inhibitors of fibril growth and protected primary cortical neuronal cultures against Aβ-induced toxicity. Next, we assessed the effects of these three inhibitors in vivo in the mThy1-APPtg mouse model of AD (8-month-old mice). We found that mitoxantrone and bithionol, but not hexachlorophene, stabilized diffuse amyloid plaques, reduced the levels of Aβ42 oligomers and ameliorated synapse loss, neuronal damage and astrogliosis. Together, our findings suggest that targeting fibril growth and Aβ seeding capacity constitutes a viable and effective strategy for protecting against neurodegeneration and disease progression in AD.

Effects and mechanism of lipoic acid on beta-amyloid-intoxicated C6 glioma cells

“…Therefore, cells become overloaded with Aβ that is generated but cannot be cleared. The majority of this excess Aβ is deposited to form neurotoxic senile plaques, considered to be one of the major causes of AD (Eleuteri et al, 2014;Mhatre et al, 2014). Thus, Aβ generation and accumulation is a key feature of AD pathogenesis.…”

Neuroprotective effects of the monoamine oxidase inhibitor tranylcypromine and its amide derivatives against Aβ(1–42)-induced toxicity

“…A long-term treatment with antidepressants is known to reduce the risk to develop AD in depressed patients (Kessing et al, 2009). No studies have been yet conducted to understand whether antidepressants can interfere with Aβ aggregation by preventing the transition from Aβ oligomers to Aβ fibrils (Eleuteri et al, 2015).…”

“…Different studies have demonstrated that in an early phase of AD pathogenesis, soluble Aβ monomers aggregate into soluble Aβ oligomers and insoluble Aβ plaques, both of which can be toxic to neurons (Klein, 2013). Aβ fibril formation occurs via multiple mechanisms involving the formation of on or off-pathway oligomers (Eleuteri et al, 2015). A direct correlation has been demonstrated between the ability of Aβ oligomers to convert into fibrils and increased Aβ-induced neurodegeneration (Jan et al, 2010).…”

“…According to this scenario we observed, with the Th-T fluorescence assay for fibril formation, a clear inhibitory effect of Aβ(1-42) fibrillogenesis with TCP and its conjugates TCP-But and TCP-Ac at 5-fold molar excess. According to the model proposed by Blackley et al (1999) and revised by Eleuteri et al (2015) we hypothesize that TCP and in particular TCP-Ac not necessarily interfere with the elongation phase of the fibrils, but they act at an intermediate level where the globular oligomeric species start to assemble. We found that TCP-Ac significantly affects the Aβ fibril formation being able to almost double the lag-phase period of Aβ aggregation.…”

Multiplex Drug Screenings to Discover Host Oriented Therapies Against Infectious Diseases

“…This suggests that it is possible to achieve effective anti-toxin and anti-Zika Bithionol doses in blood by oral administration. In addition, Bithionol was i) used to treat cerebral paragonimiasis 102 and is known to cross the brain-blood barrier 103 ; ii) reported to cross the placental barrier 104 ; and iii) was used to treat paragonimiasis in a population that included children and pregnant women 105 . All of these observations suggest that Bithionol is likely to achieve anti-Zika efficacy in humans.…”