The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy

Abstract

The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer’s disease (AD) that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive gliosis. The findings support the potential for slowing the progression of AD by abrogating tau-mediated neurotoxicity at its earliest neuropathological stages.

The mTOR signalling cascade: paving new roads to cure neurological disease

“…In the offspring produced by crossbreading 3xTg AD model mice and S6K1 knockout mice, the Aβ and tau pathology and cognitive deficits are less severe than in 3xTg mice, presumably owing to suppressed mTOR downstream signalling 100 . In a Mapt Pro301Leu mouse model of tauopathy that is reminescent of early-onset AD, rapamycin protected against tau-induced neuronal death, synaptic toxicity, microgliosis and astrogliosis 101 . Similarly, the mTOR inhibitor temsirolimus enhanced autophagy and prevented accumulation of tau and formation of neurofibrillary tangles in mutant tau transgenic mice 102 .…”

A Brief Overview of Tauopathy: Causes, Consequences, and Therapeutic Strategies

“…The mTOR inhibitor rapamycin reduces pathogenic tau and improves cognition in numerous mouse models by upregulating autophagy [87-89, 93], and prevents neuronal death in tau transgenic Drosophila [91]. While treatment of 3xTg-AD mice with rapamycin prior to tau tangle formation significantly reduces formation of tau tangles and cognitive deficits, tangles are not reduced when rapamycin is administered after tangle formation, suggesting that beneficial effects of rapamycin may require an early diagnosis [94].…”

Biotic/Abiotic Stress-Driven Alzheimer's Disease

“…However, Aβ is unlikely an initiator, and more likely a mediator of AD, so Aβ-targeted interventions should not be an eventual solution to attenuating progressive aggravation toward AD. Once infectious agents have been verified as the primordial etiological cues leading to AD, the more practical medications treating AD should at least include, for example, anti-infection agents such as minocycline (El-Shimy et al, 2015; Budni et al, 2016), anti-inflammation agents such as anhydroexfoliamycin (Leirós et al, 2015) or rapamycin (Siman et al, 2015), and anti-oxidation agents such as allicin (Zhu et al, 2015). With similar importance, modulation of gut microbiota from dysbiosis to homeostasis for the early-phase prophylaxis of AD through personalized diet and prebiotic/probiotic supplementation should also be addressed (Hu et al, 2016).…”