Compositions and methods for treating Alzheimer's disease and other brain disorders

Abstract

Pharmacological or genetic inactivation of MAGL attenuates neuroinflammation and neuropathology in animal models of AD. However, global inactivation of MAGL induces functional resistance of CB1R, thereby reducing the efficacy of drug therapy. Furthermore, global inactivation of MAGL has been shown to induce several other adverse effects, including cognitive impairment (Figure 3), indicating that global inactivation of MAGL with pharmacological inhibitors is not an optimal approach for achieving ideal therapeutic effects in AD. Other evidence suggests that selective inactivation of MAGL in astrocytes, but not neurons, attenuates neuropathology as well as synaptic and cognitive impairments following TBI. Notably, results showed that inactivation of astrocytic MAGL attenuates AD neuropathology and prevents the deterioration of LTP, spatial learning, and memory in AD animals. This indicates that the neuroprotective effect of global MAGL inactivation results primarily from limiting 2-AG degradation in astrocytes, but not neurons. Therefore, selective inactivation of astrocytic MAGL would significantly minimize potential adverse effects resulting from global inactivation-induced disruption of 2-AG degradation in neurons and other peripheral tissues, thereby resulting in better therapeutic outcomes for AD. To this end, an AAV-mediated gene silencing approach to selectively knockdown MAGL in astrocytes is presented.

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