Inducing Autophagy by Rapamycin Before, but Not After, the Formation of Plaques and Tangles Ameliorates Cognitive Deficits

Abstract

Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression.

Olfactory Functions Scale with Circuit Restoration in a Rapidly Reversible Alzheimer's Disease Model

“…Many studies have targeted APP metabolism, as a means of intervention, including both active (Schenk et al, 1999;Janus et al, 2000;Morgan et al, 2000;Lavie et al, 2004;Jensen et al, 2005) and passive (Dodart et al, 2002;Kotilinek et al, 2002;Lee et al, 2006) immunotherapy, use of secretase inhibitors (De Strooper et al, 2010;Fukumoto et al, 2010;Chang et al, 2011), efforts to enhance clearance of ␤-amyloid (Lim et al, 2000;Heneka et al, 2005;Zelcer et al, 2007;Wesson et al, 2011;Cramer et al, 2012), and also improvement of autophagic-lysosomal proteolytic function (Butler et al, 2011;Majumder et al, 2011;Yang et al, 2011). Although some evidence does support that a reduction of amyloid burden can ameliorate learning and memory deficits (Janus et al, 2000;Morgan et al, 2000;Lavie et al, 2004;Jensen et al, 2005), it is unclear whether the improvement in performance correlates with changes in underlying circuitry.…”

Rapalogs and mTOR inhibitors as anti-aging therapeutics

“…Third, rapamycin has been shown to delay multiple age-related changes in mice, including loss of stem cell function (25), cognitive decline (28), retinopathy (29), accumulation of subcellular alterations in the myocardium, liver degeneration, endometrial hyperplasia, tendon stiffening, and decline in physical activity (30). Moreover, rapamycin is therapeutic in rodent models of cardiac hypertrophy (31,32) and neurodegenerative diseases (33)(34)(35), conditions that affect aging humans. While cancer prevention clearly plays a major role in the survival benefit conferred by rapamycin, it is important to understand that cancer is an agerelated disease, and its prevention is an expected consequence of any therapy that slows aging.…”

Autophagy and genomic integrity

“…29,114 Deletion of parkin increases ROS generation due to accumulation of dysfunctional organelles, resulting in mtDNA and nDNA damage, which is the basis for parkin deficiency-associated Parkinson's disease. 115,116 In this sense, induction of autophagy has given promising results in mouse models of Alzheimer's disease 117 and other neurodegenerative diseases. 118 Further, the increased genomic instability observed in parkin-deleted cells could also be explained by the observation that parkin translocates from the cytosol to the nucleus where it participates in DDR after DNA damage.…”