Tor as a key regulator of neuronal and vascular function in mouse models of Alzheimer?s Disease

VERONICA GALVAN; S. HUSSONG; J. HALLORAN ; R. BURBANK; K. FISCHER; S. AUSTAD; A.L. LIN; J. CUVILLIER; C. VAN SKIKE; CARLOS POMILIO

Congreso; Alzheimer`s Association International Conference 2016; 2016

Background: We recently showed that chronic treatment with the target-of-rapamycin (TOR) inhibitor rapamycin, a drug that extends lifespan and delays aging in mice, halted and even reversed Alzheimer?s (AD)-like memory deficits, decreased Ab, and restored cerebral blood flow (CBF) in brains of hAPP(J20) and Tg2576 mice modeling the disease. Reducing TOR activity also restored cognitive function and CBF in mice modeling atherosclerosis, as well as in 36 month-old rats. Attenuating TOR activity was associated with the recovery of cortical network activation and functional hyperemia evoked by somatosensory stimulation. Our data indicate that the mechanisms by which TOR attenuation restores CBF, neuronal activity, and cognitive function may be common to different models of age-associated neurological disease and to brain aging, and singled out (a) vascular NO release, and (b) synaptic bouton remodeling as key mechanisms by which TOR attenuation blocks AD-like progression in mice. Methods:To delineate the mechanisms by which TOR regulates synaptic remodeling during aging and inADwe used rapamycin in very old rats, and advanced tissue-specific genetic tools to reduceTORcomplex1assembly specifically in neurons of adult mice. Results: Moderate, but not drastic reduction of TORC1 assembly in neurons, to levels similar to those achieved by rapamycin treatment, promoted synaptic remodeling and increased autophagy, potentially increasing synaptic vesicle recycling. This was associated with enhanced memory and increased brain glucose uptake, suggestive of increased brain glucose metabolism.We propose that attenuation of TOR in (a) brain vascular endothelial cells and in (b) Ab-producing parenchymal neurons by pharmacological or genetic means act synergistically to slow the progression of AD dysfunction through the restoration of (1) NO-dependent vasodilation and CBF, increasing vascular Ab clearance, and (2) by increasing autophagy at synapses, leading to synaptic bouton remodeling, decreased Ab release, and restored neuronal function in AD. Conclusions:Relieving TOR-dependent inhibition of synaptic remodeling and neurovascular NO release may be critical synergistic mechanisms by which rapamycin or genetic TORC1 knockdown preserve network activation, functional hyperemia and cognitive function during aging and in models of AD and other dementias. TOR inhibition may have promise as therapy for AD and potentially other neurodegenerations.