Targeting autophagy as a therapeutic strategy to prevent dopamine neuron loss in early stages of Alzheimer disease

Abstract

Alzheimer disease (AD) is a neurodegenerative disorder for which no approved medication exists. AD is characterized by worsening cognitive and non-cognitive symptoms, and research in the AD field strives to identify very precocious brain alterations leading to an irreversible condition. Recently it has been demonstrated that several early AD symptoms are paralleled with degeneration of neurons producing dopamine (DA), a neurotransmitter involved in the regulation of cognitive and non-cognitive functions. Actually, we found that ventral tegmental area (VTA) DA neurons degenerate early in a validated AD mouse model (Tg2576). Here, we summarize new data showing how macroautophagy/autophagy impairment - due to enhanced activity of the ABL/c-Abl kinase - might cause the DA neuron loss. We also proved that nilotinib, an ABL inhibitor, restores autophagy flux, thus preventing VTA neurodegeneration. Most notably, from a clinical point of view, nilotinib, by preventing DA neuronal loss, preserves DA outflow in VTA-projecting areas, improving Tg2576 behavioral phenotypes. Our findings shed light on the mechanism involved in DA neurodegeneration, revealing that autophagy represents a viable therapeutic target in early AD.

Keywords: ABL/c-ABl; Alzheimer; Tg2576; hippocampus; macroautophagy; midbrain; nilotinib; pre-plaque stage; tyrosine kinase; ventral tegmental area.

Figure 1.

Nilotinib exerts neuroprotective effect on VTA dopamine neurons by the improvement of autophagic flux. (A) VTA dopamine neurons from 3-months-old Tg2576 mice show increased phosphorylated ABL levels and impairment in autophagy machinery, which could cause accumulation of intracellular Aβ and increase in spontaneous firing frequency. During the disease progression, firing frequency alteration become more severe and cell shrinkage occurs. All these physiological alterations are strictly related with VTA neurodegeneration, which leads to a reduction of DA levels in VTA-projecting areas, such as the hippocampus, and cognitive deficits. (B) VTA DA neurons from nilotinib-treated mice show reduction of both ABL phosphorylated levels and autophagosomes accumulation. The improvement in autophagy efficiency promotes the reduction of Aβ and improves neuronal health, as demonstrated by normal firing frequency and preserved soma shape. Nilotinib exerts a neuroprotective effect on VTA DA neurons, thus preserving DA outflow in hippocampus and ameliorating memory functions in Tg2576 mice