Novel Approaches for the Treatment of Alzheimer's and Parkinson's Disease

Abstract

Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer's and Parkinson's diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.

Keywords: Alzheimer; Parkinson; aging; neurodegeneration; neurogenesis; neuroinflammation; novel approaches.

Figure 1

The general pathways involved in neurodegenerative diseases. Physiological processes like endosomal-lysosomal autophagy, neuroinflammatory responses, mitochondrial homeostasis, proteostasis, and metabolic profiling (proteome and lipidome) are dysregulated in neurodegenerative diseases (red arrows). Alterations in homeostasis mechanisms like the endosomal–proteosomal–autophagy pathway and an increase in misfolded protein aggregation are major factors in Alzheimer’s disease (AD) and Parkinson’s disease (PD). The oxidative stress caused by mitochondrial dysfunction and dysregulation of endogenous antioxidant mechanisms is influenced by the level of free radicals. The positive feedback loop between oxidative stress, misfolded proteins, and mitochondrial dysfunction is crucial in therapeutic interventions. Furthermore, pre- and post-synaptic integrity loss due to alterations in calcium homeostasis together with the above pathways is an important mechanism involved in proapoptotic pathway activation. In addition, the remains of dead cells and the misfolded proteins released into the extracellular environment provoke glia-activation, which releases cytokines and free radicals, exacerbating neuronal death, which establishes another negative feedback loop between neurodegeneration and neuroinflammation. Finally, these alterations also affect neurogenesis in Alzheimer’s disease (AD) and Parkinson’s disease (PD).

Figure 2

Novel treatment strategies for AD. The most relevant approaches to restore altered pathways in AD are shown with green arrows when processes are improved or T-bars when inhibited. The novel acetylcholinesterase (AChE) inhibitors BPT and Kojo tacrine affect autophagy impairment, misfolded proteins, and their aggregates in the intracellular and extracellular brain environment. A03 compound has an antagonist influence on the NMDAR-mediated pathways involved in increasing SIRT1 expression. Other target strategies of autophagy impairment are CDK5 inhibitors and small lanthionine ketamine-ethyl ester (LKE) molecules against increased CRMP2 expression. Neurogenesis impairment is improved by P021, IRL-1620, trehalose, metformin, LKE, amodiaquine, and allopregnanolones (AP) (BR297) treatments. IRL-1620 increases the clearance of Aβ in the bloodstream by influencing the Endothelin B (ETB) receptor. P021 and trehalose have positive influences on misfolded proteins. Diethyl(3,4-dihydroxyphenethylamino) (quinolin-4-yl)methylphosphonate (DDQ) and AP (BR297) increase mitochondrial biogenesis and Aβ clearance. Minocycline increases anti-inflammatory responses and decreases pro-inflammatory responses. Metal ions homeostasis alteration can be rescued by PBT-1, PBT-2, 4-(1-benzylpiperidin-4-yl)thiosemicarbazones (BPT) derivatives, and deferoxamine (DFO).

Figure 3

Novel treatment strategies in PD. The most relevant approaches to restore altered pathways in PD are shown with green arrows when processes are improved or T-bars when inhibited. The compounds used to target α-Syn aggregation are antisense oligonucleotides against these protein aggregates (ASO), oligomer modulators (Anle138, SynucleanD and NPT200-11), and cAbl inhibitors (Nilotinib). Pathogenic α-Syn spreading can be avoided by 14-3-3 protein activation and the use of active (PD03A) or passive (PRX002 and BIIB054) immunization. Autophagy impairment is targeted by stimulation with TFEB activators or Beclin-1 activity inducers (KYP-2047), but also by the activation of lysosomal activity with GBA activators (Ambroxol), glucosylceramide synthase (GCS) inhibitors (GZ/SAR40261), GCase activators (NCGC607), and acid nanoparticles (PLGA-aNPs). Ca²⁺ channel inhibitors (Israpidine) preserve physiological levels that are altered in PD. Mitochondrial biogenesis can be activated with Nrf2 activators (BG12 and triterpenoids). Nip3-like protein X (NIX) activators, cAbl inhibitors (STI-571), and deubiquitinases (DUBs) inhibitors (USP30 inhibitors) increase degradation of damaged mitochondria. PD-linked mutations affecting mitochondria can be modified by gene therapy. Using a pituitary adenylate cyclase-activating polypeptide (PACAP) receptor agonist (Maxadilan), phosphodiesterase 7 (PDE7) inhibitors (S14), or peroxisome proliferator-activated receptor-γ (PPARγ) inhibitors (glitazones) could target neuroinflammation. The activation of neuronal survival pathways can be improved by administration of neurotrophic factors (GDNF, MANF, CDNF, and PDGF-BB). Nuclear receptor related 1 (Nurr1) activators, cAMP response element binding protein (CREB) activators (Rolipram), glycogen synthase kinase-3 (GSK3) activators (Tideglusib), or induced pluripotent stem (iPS) cell transplantation might restore neurogenesis impairment.