Inhibition of the MID1 protein complex: a novel approach targeting APP protein synthesis

Abstract

Alzheimer’s disease (AD) is characterized by two neuropathological hallmarks: senile plaques, which are composed of amyloid-β (Aβ) peptides, and neurofibrillary tangles, which are composed of hyperphosphorylated tau protein. Aβ peptides are derived from sequential proteolytic cleavage of the amyloid precursor protein (APP). In this study, we identified a so far unknown mode of regulation of APP protein synthesis involving the MID1 protein complex: MID1 binds to and regulates the translation of APP mRNA. The underlying mode of action of MID1 involves the mTOR pathway. Thus, inhibition of the MID1 complex reduces the APP protein level in cultures of primary neurons. Based on this, we used one compound that we discovered previously to interfere with the MID1 complex, metformin, for in vivo experiments. Indeed, long-term treatment with metformin decreased APP protein expression levels and consequently Aβ in an AD mouse model. Importantly, we have initiated the metformin treatment late in life, at a time-point where mice were in an already progressed state of the disease, and could observe an improved behavioral phenotype. These findings together with our previous observation, showing that inhibition of the MID1 complex by metformin also decreases tau phosphorylation, make the MID1 complex a particularly interesting drug target for treating AD.

Metformin and cognition from the perspectives of sex, age, and disease

“…Many recent studies explored AMPK-dependent, AMPK-independent, and energy independent effects of metformin in neuronal activity, differentiation, toxicity, autophagy, and survival. These differential effects on neurons were dose, duration, and disease-dependent (Aatsinki et al 2014;Bayliss et al 2016;Canto et al 2009;Fatt et al 2015;Ge et al 2017;Hawley et al 2010;Isakovic et al 2007;Jang and Park 2018;Katila et al 2017;Khedr et al 2018;Kickstein et al 2010;Matthes et al 2018;Ou et al 2018;Potts and Lim 2012;Price et al 2012;Sesen et al 2015;Song et al 2015;St-Pierre et al 2006;Wang et al 2012;Wang et al 2018b;Yan et al 2017;Zhang et al 2016;Zhu et al 2015).…”

“…The color-coding in this predictive model is a summary of existing evidence on known mediators of metformin-induced cognitive changes. A more substantial clinical investigation should aim to extend these data to achieve a more accurate precision medicine approach to metformin pharmacotherapy pathways (Matthes et al 2018;Ou et al 2018), which suggest that the experimental design and model plays a critical role in outcome and conclusion.…”

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm

“…Our metformin treatment paradigm in the mouse provides guidance for preclinical studies of metformin on aging and aging-related diseases. Treatment of metformin in drinking water has been commonly used in mouse studies at the concentrations of 0.5, 2, and 5 mg/ml or final dose of 50, 100, and 250 mg/kg body weight [41][42][43][44][45][46][47][48][49][50][51]. Treatment of 2 mg/ml metformin in drinking water has been found to increase survival time in male mouse model of Huntington's disease [41], increase motor unit survival in tibialis anterior muscles of female SOD1 amyotrophic lateral sclerosis mice without any significant effect on disease onset, progression or survival in male or female SOD1 ALS mice [48], increase generation of both intracellular and extracellular Aβ species [46], reduce tau phosphorylation but promote tau aggregation and exacerbates abnormal behavior in P301S human tau transgenic mice [49,52], improve locomotor function while impair long-term memory in male C57B/L6 mice [50,53].…”

“…Treatment of 2 mg/ml metformin in drinking water has been found to increase survival time in male mouse model of Huntington's disease [41], increase motor unit survival in tibialis anterior muscles of female SOD1 amyotrophic lateral sclerosis mice without any significant effect on disease onset, progression or survival in male or female SOD1 ALS mice [48], increase generation of both intracellular and extracellular Aβ species [46], reduce tau phosphorylation but promote tau aggregation and exacerbates abnormal behavior in P301S human tau transgenic mice [49,52], improve locomotor function while impair long-term memory in male C57B/L6 mice [50,53]. Treatment of 5 mg/ml metformin in drinking water significantly reduced Aβ plaque burden and improved water maze performance in male and female APP/PS1 mice [51]. Treatment of 100 mg/kg/day metformin in drinking water has been found to increase mean and maximum life span of female transgenic HER-2/neu mice [42] and female SHR mice [43], decrease mean life span of male 129/Sv mice while increase mean life span female 129/Sv mice [45].…”

MicroRNAs miR-19, miR-340, miR-374 and miR-542 regulate MID1 protein expression

“…Another interesting observation is that a significantly decreased expression of miR-19b-3p has been reported to coincide with increased protein expression of BACE1 in Alzheimer’s disease, although miR-19b-3p does not directly target BACE1 [ 72 ]. We show here that miR-19b-3p targets MID1, a protein that we have previously shown to induce protein expression of two mRNAs that are crucial for the development of amyloid plaques in Alzheimer’s disease, namely BACE1 [ 4 ] and APP [ 73 ]. Furthermore, we have observed increased expression of MID1 in Alzheimer’s disease brains [ 74 ].…”