The neuroprotective effects of glucagon-like peptide 1 in Alzheimer's and Parkinson's disease: An in-depth review

Abstract

Currently, there is no disease-modifying treatment available for Alzheimer's and Parkinson's disease (AD and PD) and that includes the highly controversial approval of the Aβ-targeting antibody aducanumab for the treatment of AD. Hence, there is still an unmet need for a neuroprotective drug treatment in both AD and PD. Type 2 diabetes is a risk factor for both AD and PD. Glucagon-like peptide 1 (GLP-1) is a peptide hormone and growth factor that has shown neuroprotective effects in preclinical studies, and the success of GLP-1 mimetics in phase II clinical trials in AD and PD has raised new hope. GLP-1 mimetics are currently on the market as treatments for type 2 diabetes. GLP-1 analogs are safe, well tolerated, resistant to desensitization and well characterized in the clinic. Herein, we review the existing evidence and illustrate the neuroprotective pathways that are induced following GLP-1R activation in neurons, microglia and astrocytes. The latter include synaptic protection, improvements in cognition, learning and motor function, amyloid pathology-ameliorating properties (Aβ, Tau, and α-synuclein), the suppression of Ca²⁺ deregulation and ER stress, potent anti-inflammatory effects, the blockage of oxidative stress, mitochondrial dysfunction and apoptosis pathways, enhancements in the neuronal insulin sensitivity and energy metabolism, functional improvements in autophagy and mitophagy, elevated BDNF and glial cell line-derived neurotrophic factor (GDNF) synthesis as well as neurogenesis. The many beneficial features of GLP-1R and GLP-1/GIPR dual agonists encourage the development of novel drug treatments for AD and PD.

Keywords: Alzheimer’s disease; GLP-1; Parkinson’s disease; amyloid beta; brain glucose hypometabolism; insulin resistance; mitochondrial dysfunction; neuroinflammation.

FIGURE 1

Dynamics between IR, GLP-1R and PICR-signaling in neurons. 1 The release of pro-inflammatory cytokines and the activation of PICRs on neurons induce the kinases IKKβ, PKR, and JNK to trigger the inhibitory Ser-phosphorylation of IRS-1 and neuronal insulin resistance in AD and PD. Aβ was further shown to drive IR clustering and endocytosis. In addition, Aβ provokes intracellular Ca²⁺ accumulation by external (VDCCs/NMDARs) and internal means (ER). The latter reinforces the desensitization of the insulin pathway, blocks protein translation (eIF2α/mTORC1 pathway) and activates the Ca²⁺-sensitive calpain to impair autophagy, interfere with the synaptic function and promote the hyperphosphorylation of Tau by cleaving p35 into the Cdk5-activating binding partner p25. Further consequences of inflammation and insulin resistance include reduced IDE1 expression, enhanced APP and BACE1 expression, Aβ overproduction and amassment, the loss of neuroprotective PI3K/Akt and CREB signaling, GSK-3β hyperactivity and concomitant Tau hyperphosphorylation. Crucially, the impairment of the Akt/mTor pathway following insulin resistance impedes the expression of glycolytic enzymes, thus enforcing bioenergetic impairments and glucose hypometabolism. 2 In contrast to the IR, the GLP-1R does not desensitize in neurons. When activated, the GLP-1R stimulates PI3K/Akt/mTORC1, cAMP/PKA, MEK/ERK, and CREB/BDNF-signaling to ameliorate the Aβ (section “GLP-1R agonists are neuroprotective and prevent amyloid beta accumulation in vivo”) and Tau (section “GLP-1R mimetics suppress Tau hyperphosphorylation and aggregation during AD”) pathologies through various mechanisms, suppress excessive Ca²⁺ influx and ER stress (not shown; details in sections “GLP-1 mimetics suppress Ca2+ deregulation by amyloid beta and excitotoxicity” and “GLP-1 analogues counteract endoplasmic reticulum stress”), restore insulin signaling (section “Insulin resistance and the neuronal energy metabolism”) by aiding the clearance of Aβ, normalize the autophagy function by raising the expression of autophagy modulators via mTORC1 (Atg3, Atg7, Beclin-1) (section “Autophagy and mitophagy”), elevate neurogenesis (section “GLP-1R agonists promote neurogenesis”) and promote the synaptic function, plasticity and memory (section “Pro-cognitive effects”). Importantly, the activation of GLP-1R on microglia and astrocytes induces the anti-inflammatory M2 phenotype and suppresses inflammatory cytokine production (not shown; see section Inflammation), thus preventing insulin resistance.

FIGURE 2

Pro-mitochondrial, anti-oxidative and anti-apoptotic effects of GLP-1 in neurons. 1 In AD, Aβ is translocated into mitochondria via TOM and accumulates in cristae, leading to elevated ROS production through the interaction with AβAD and the impairment of the TCA enzymes PDH/α-KGDH as well as complex VI, but also I and II, of the ETC. Moreover, Aβ triggers mitochondrial Ca²⁺ instream and swelling by binding to cyclophilin D and stimulates mitochondrial fragmentation by altering the expression of fusion/fission-modulating proteins. 2 As common for both neurodegenerative diseases, pro-inflammatory cytokine signaling across PICRs stimulates JNK to activate BIM and Bax-expression via p53. While dopamine is packaged into synaptic vesicles by VMAT2 in dopaminergic neurons, JNK may induce COX2 to encourage the production of reactive dopamine quinones. Pathologic alterations in the expression and localization of GAPDH as well as insulin resistance-associated impairments in the expression of glycolytic enzymes may accelerate the build-up of the AGE and ROS-generating compound methyl glyoxal. The latter was shown to react with dopamine to create ADTIQ, which amasses in nigrostriatal brain areas and, similar to the PD-toxins MPTP, 6-OHDA or rotenone, inhibits complex I of the ETC to stimulate ROS production in neurons. Metal ion accumulation in the brain, in particular the iron-mediated ROS production, lipid peroxidation, mitochondrial dysfunction and ferroptosis are implicated in AD and PD. 3 Crucially, as apparent in AD, Aβ and ROS activate GSK-3β, which promotes the trafficking of GSK-3β into mitochondria to induce the opening of miPTPs, interfere with ATP production/OXPHOS by inhibiting PDH and ETC complexes and drive apoptosis by stimulating the p53-mediated synthesis of Bax and inactivating the anti-apoptotic Mcl-1. GSK-3β further suppresses NRF2-driven anti-oxidative gene transcription and elicits the degradation of PGC-1α via SCF-Cdc4 E3 ligase. 4 Metabolic stress following TCA/OXPHOS/ETC impairments and enhanced ROS load ultimately trigger miPTP opening/Ca²⁺ deregulation, deformation, MMP loss, ATP depletion and Bax/Bak-mediated pore formation in mitochondria, resulting in APAF1/Caspase 9/Caspase 3-mediated apoptosis. 5 The induction of the GLP-1R prevents all of the pathological alterations in neurons described above. First, the activation of the survival modulator Akt leads to the direct inactivation of GSK-3β, caspase 3, Bad and FOXOs. The Akt-induced stimulation of mTOR/mTORC1, in conjunction with various other transcription factors, augments the global protein translation, including that of the dopamine-synthesizing TH and VMAT2 in dopaminergic neurons, the GSH-producing GCLc, the mitochondrial biogenesis and fusion/fission-navigating PGC-1α as well as glycolytic/TCA enzyme expression. Notably, Akt further phosphorylates HKII to recruit it to the outer mitochondrial membrane to prevent miPTP opening, whereas GSK-3β induces the liberation of HKII, evoking the opposite result (not shown) (Rasola et al., 2010). Second, cAMP/PKA-signaling inhibits DLP-1, thus suppressing mitochondrial fragmentation. Third, PI3K/Akt, cAMP/PKA, and MEK/ERK-signaling lead to the induction of CREB to improve BDNF/GDNF expression (chapter “Other growth factors”), elevate the expression of anti-apoptotic Bcl-2/Mcl-1, upregulate anti-oxidative defense genes, and encourage deoxyribonucleic acid (DNA) repair via APE1. Fourth, GLP-1 blocks pro-inflammatory cytokine production by glial cells (chapter “Inflammation”) and, hence, PICR/JNK-signaling in neurons. Given the pro-mitochondrial and dopamine-enhancing effects, animal and clinical studies support the benefits of GLP-1 treatment in PD (see chapter “GLP-1 mimetics rescue nigrostriatal dopamine neuron death and dopamine depletion in PD”). For the anti-ferroptosis-associated effects of GLP-1 in AD and PD, see section GLP-1 analogs protect from iron and dopamine-induced oxidative stress and ferroptosis.