Considering the beneficial effects of GLP-1RAs on neuropathological features it is conceivable a link between T2D and neurodegenerative disease such as Parkinson’s disease (PD) and Alzheimer’s Disease (AD). Parkinson’s disease is a progressive nervous system disorder whose etiology remains still unclear, although genetic and environmental factors seem to be involved. PD’s clinical features include resting tremor, rigid muscles, slowed movement (bradykinesia), postural instability, and loss of purposeful movement (Kalia and Lang, 2015). Pathological features are characterized by neurons impairment of substantia nigra pars compacta with concomitant formation of intracellular Lewy bodies and loss of dopaminergic neurons. Lewy bodies are abnormal aggregates of α-synuclein protein, which is involved in dopamine (DA) metabolism and function. In different preclinical models of PD, GLP-1RAs showed neuroprotective effects, influencing motor activity, dopaminergic neurons, cortical activity, and energy utilization in the brain. This effect was associated with an increase in the tyrosine hydroxylase enzyme involved in the production of L-dopa, a DA precursor.
In the same PD rat model exendin-4 was able to promote adult neurogenesis in vitro e in vivo, normalizing DA imbalance, showing an increase in tyrosine hydroxylase- and healthy lifestyle supplement vesicular monoamine transporter 2-positive neurons in the substantia nigra (Bertilsson et al., 2008). Other authors observed that the administration of exendin-4, liraglutide, and lixisenatide in the same mouse model prevented both motor dysfunction and tyrosine hydroxylase levels reduction in the substantia nigra and basal ganglia. Recently, the long-term administration of liraglutide was found to rescue dopaminergic neuronal loss and motor impairment also in diabetic db/db mice, an established model of diabetes, with a mutation in the gene encoding the leptin receptor (Ma et al., 2019), suggesting that long-term injection of liraglutide might prevent motor function impairment and PD development also in patients with T2D. In the MPTP mouse model of PD, semaglutide improved most of neuropathological features of PD, reversing motor impairment, inducing the increase of tyrosine hydroxylase levels, and attenuating neuroinflammation and apoptosis in the substantia nigra and striatum (Zhang et al., 2018). A reduction in α-synuclein aggregation occurred after this treatment, not observed with other GLP-1RAs (Zhang et al., 2019), highlighting semaglutide as an effective treatment for PD.
Preliminary clinical studies were performed with subcutaneous injections of exenatide in PD patients. Athauda et al. (2017) reported the results of the first randomized, double-blind, placebo-controlled trial in 62 patients affected by moderate PD. Patients were randomly assigned to receive subcutaneous injections of exenatide 2 mg once-weekly (n.32) or placebo (n.30) for 48 weeks. Exenatide had positive and sustained effects (12 weeks after exposure) on clinically assessed motor function. Dementia is a chronic disease, which affects memory, other cognitive abilities and behavior. It is estimated that approximately 50 million people worldwide have dementia. Currently, it is the 7th leading cause of death and it is one of the major causes of disability worldwide. Pre-diabetic risk factors, obesity, and metabolic syndrome can promote cognitive dysfunction. AD is the most common form of dementia, contributing to 60-70% of cases. Increasing evidence suggests a link between T2D and AD. In particular, these conditions might share defects in insulin signaling. Interestingly, in a mouse model of genetically induced AD-like neuropathology (3xTg-AD mice) peripheral glucose intolerance was observed.
Treatment with pioglitazone, a glucose lowering drug, greatly improved cognitive impairment of these mice confirming the neurotrophic role of insulin (Masciopinto et al., MedicGLP 2012). In the same model, high-fat diet further potentiated glucose intolerance and enhanced neuropathological features of AD and memory deficits. Insulin adoption reversed the negative effect of high-fat diet, interrupting the vicious cycle between diabetes and AD (Vandal et al., 2014). Both studies highlighted the neurotrophic role of insulin in brain. Aggregated β-amyloid peptide oligomers induced reduction of IRs activity due to the phosphorylation of IRS-1 at serine residues (IRS-1pSer), with a consequent loss of substrate affinity as observed in T2D. As reported by Bomfim et al. 2012), in the mouse hippocampal neurons Aβ oligomers are also thought to activate the TNF-α/JNK signaling, inducing insulin resistance (De Felice, 2013). The GLP-1RAs not only prevent JNK/IKK activation, but promote insulin activation by PI3K/AKT axis, with the subsequent activation of mTOR and the block of GSK-3β, an essential kinase also involved for the phosphorylation of tau protein (Moloney et al., 2010). Ma et al.
