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Bild, W.;  Vasincu, A.;  Rusu, R.;  Ababei, D.;  Stana, A.B.;  Stanciu, G.D.;  Savu, B.;  Bild, V. Impact of the Renin-Angiotensin System on Neurodegenerative Diseases. Encyclopedia. Available online: https://encyclopedia.pub/entry/31820 (accessed on 23 April 2024).
Bild W,  Vasincu A,  Rusu R,  Ababei D,  Stana AB,  Stanciu GD, et al. Impact of the Renin-Angiotensin System on Neurodegenerative Diseases. Encyclopedia. Available at: https://encyclopedia.pub/entry/31820. Accessed April 23, 2024.
Bild, Walther, Alexandru Vasincu, Răzvan-Nicolae Rusu, Daniela-Carmen Ababei, Aurelian Bogdan Stana, Gabriela Dumitrița Stanciu, Bogdan Savu, Veronica Bild. "Impact of the Renin-Angiotensin System on Neurodegenerative Diseases" Encyclopedia, https://encyclopedia.pub/entry/31820 (accessed April 23, 2024).
Bild, W.,  Vasincu, A.,  Rusu, R.,  Ababei, D.,  Stana, A.B.,  Stanciu, G.D.,  Savu, B., & Bild, V. (2022, October 28). Impact of the Renin-Angiotensin System on Neurodegenerative Diseases. In Encyclopedia. https://encyclopedia.pub/entry/31820
Bild, Walther, et al. "Impact of the Renin-Angiotensin System on Neurodegenerative Diseases." Encyclopedia. Web. 28 October, 2022.
Impact of the Renin-Angiotensin System on Neurodegenerative Diseases
Edit

The renin-angiotensin-aldosterone system (RAS) is an endocrine axis which has important peripheral physiological functions (blood pressure and cardiovascular homeostasis, water and sodium balance, and systemic vascular resistance). In addition to the systemic action of RAS, recent research highlights its paracrine and autocrine actions in many tissues, including the central nervous system. The complex is located intracellularly and is involved in various intracellular processes.

neurodegenerative renin angiotensin (1–7) brain RAS Alzheimer’s Huntington’s multiple sclerosis

1. Introduction

Prorenin can be found in juxtaglomerular (JG) cells, which are specialized cells from within the afferent arterioles of the kidney. By activating JG cells, prorenin is cleaved into its active form called renin. It, in turn, will act on angiotensinogen (Angt), which is produced in the liver and can be found in plasma. This will lead to the formation of angiotensin I with a decapeptide structure [1]. Angiotensin (Ang) I is converted into Ang II through the action of angiotensin-converting enzyme 1 (ACE1), also called kininase II, an enzyme that is also involved in the degradation of bradykinin (BK) [2][3][4]. Accumulation of BK leads to a series of side-effects specific for ACE inhibitor therapy (e.g., cough and angioedema). The effects of RAS are mediated by Ang II following the stimulation of Ang II type 1 (AT1) receptors: sodium and water retention, vasoconstriction, and aldosterone synthesis [5]. Other components of RAS are angiotensin-converting enzyme 2 (ACE2), angiotensin fragments (Ang (1–7), Ang III, Ang IV), as well as different receptors (AT2, AT4, MAS) [6].
It is known that RAS hyperactivation generally has deleterious effects on neurons in culture and in vivo, mediated by its pro-inflammatory and pro-oxidant actions, and achieved mainly through the AT1 receptor (AT1R), but also intracellularly or through the multitude of metabolically active peptide fragments of Angt, Ang I or II that are formed via the action of tissue or circulating enzymes [3]. Another important aspect is that RAS itself has very efficient self-modulation modes inside AT2R, Ang (1–7), Ang IV/AT4R, etc. [7]. However, in many cases, patients receive ACE inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the context of hypertension and heart or kidney disease. Modulating RAS in the context of BNDs needs to be properly addressed by healthcare providers.

2. RAS in the CNS

The impermeable nature of the blood-brain barrier (BBB) for RAS components through brain regions imposes a separation between tissue components from intraneuronal ones. However, a multitude of studies demonstrate the existence of a RAS system of the CNS, complete with enzymes, precursors, and receptors of all kinds, and even peptides and/or receptors that are no longer found in other tissues, such as Ang IV/AT4R [8][9][10].
It is well known that the systemic RAS is an endocrine system responsible for the regulation of homeostasis and the brain-localized RAS is involved in cognitive processes, such as memory and learning. These two types of RAS (systemic and brain) interact with one another [2][7][11][12]. Most brain regions do not have access to peripheral RAS, although the forebrain pathway allows peripheral access of RAS components, whereas the BBB restricts the peripheral RAS components from reaching the brain [3]. This pathway connects the circumventricular organs (CVOs), which are considered brain regions lacking the BBB, to the medial preoptic, supraoptic, and paraventricular nuclei. The brain is responsive to both circulating Ang II acting on its receptors found in BBB-deficient CVOs, as well as to centrally generated Ang II [13].
Angt is found predominantly in the subfornical organ, paraventricular nucleus, nucleus of the solitary tract, and rostral ventrolateral medulla, but also in the ventrolateral medulla, hypoglossal nuclei, thalamus, hypothalamus, forebrain, and brain stem [14][15].
A major component of RAS in the nervous system is ACE. It is identifiable everywhere in the CNS, mainly due to its association with vascularization, but there is countless evidence that it exists and functions even in neurons and glia [16]. ACE2 is the variant that transforms Ang II into Ang (1–7) as well as Ang I in Ang (1–9), both with neuroprotective effects [17].
Brain RAS has a different importance compared with systemic RAS, being involved in cerebroprotection, stress, depressive disorder, and memory consolidation [18][19].
AT1R, AT2R, and MasR are located on the cell membranes, mitochondria, and nuclei [20]. RAS receptors are widespread in both neurons as well as in the three types of glial cells mentioned above. It has been shown that neurons have four main Ang Rs located in mitochondria and nuclei, such as AT1R, AT2R, MasR, and AT4R [20][21]. Type 1 and type 2 Ang Rs can be found along the spinal cord, as well as in different areas in the brain [22]. AT1R is expressed in the CNS by astrocytes, microglia, and even by neurons, particularly DA neurons. AT1R is expressed intracellularly, inside the nuclei and its membrane, as well as in the endoplasmic reticulum membrane [23].
Although Ang II/AT1R signaling has neurotoxic effects and can cause cognitive impairment due to vasoconstriction, inflammation, oxidative stress, proliferation, and cell death, Ang II/AT2R and Ang (1–7)/MasR promote neuroprotection and counteract the effects of AT1R activation. AT4Rs are located in the sensory and cognitive neuronal regions and are involved in learning and memory processes and mediate acetylcholine (Ach) and dopamine (DA) release [14].
AT1Rs are located in the hippocampus, cortex, and basal ganglia. Ang binds to this type of receptor and induces conformational changes of the receptor proteins with the activation of a G protein, followed by mediation of signal transduction. AT1Rs are G protein-coupled receptors that, in the presence of Ang II, activate Gαq protein signaling followed by dissociation of the Gαq domain. This subunit activates phospholipase C (PLC) involved in the production of diacylglycerol (DAG) and inositol triphosphate (IP3) through the metabolism of phosphatidylinositol biphosphate (PIP2). The binding of IP3 to endoplasmic reticulum receptors promotes calcium release into the cytoplasm [3][19][24].
AT2Rs share structural characteristics with members of the 7-transmembrane receptor family, belonging to the family of G protein-coupled receptors. They are widespread in the brain, showing very high densities in structures such as the amygdala, thalamus, putamen, and tegmental area [19]. The pro-inflammatory and pro-oxidant effects of Ang II mediated by AT1Rs are counteracted by activation of AT2Rs by Ang II and Mas Rs by Ang (1–7). However, an increase in AT1R expression and decrease in AT2R expression have been observed in the aging brain, which could contribute to the increased vulnerability of neurons [10]. Numerous studies have shown that AT1R and NADPH-oxidase expression can be decreased by activating AT2R, leading to decreased inflammatory responses [25].
Ang (1–7) is a heptapeptide with a protective role, capable of counteracting cellular senescence and inflammation as hallmarks of vascular aging. This peptide has actions opposite to those produced by Ang II by binding to the G protein-coupled Mas R [26]. In the brain, Ang (1–7) has been shown to counteract the pro-apoptotic effects of Ang II [11], stimulating cerebral angiogenesis and proliferation of cerebral endothelial cells, which has been confirmed in animal models. Ang (1–7) perfusion for 4 weeks in rats resulted in improved oxygen and blood supply, stabilizing brain energy status with reduced neuronal consequences. Regarding its neuroprotective role, Ang (1–7) also acts through other Mas/nitric oxide synthase (eNOS)-dependent mechanisms, modulating oxidative stress and inflammatory response [26][27]. It was shown that high levels of ACE2 cause Ang (1-7) synthesis. This enzyme is responsible for enhancing cognitive processes and its deficiency leads to pro-oxidant effects [11].
Ang IV, a metabolite of Ang II and its receptor AT4, is a membrane protein. It is known as insulin-regulated aminopeptidase (IRAP) type II, localized in the brain on neurons in the hippocampus, cortex, and basal ganglia, and is not a G-protein coupled receptor [3][28]. In an AD mouse model, activation of brain AT4Rs antagonized cognitive impairments caused by A-β pathology, suggesting that Ang IV and its analogues could be considered as therapeutic targets [28]. Metabolism of Ang II to Ang IV is the most likely underlying cause of beneficial effects, such as improved cognitive processes, which have been observed in animal model testing [29].

3. Renin-Angiotensin-Aldosterone System and Parkinson’s Disease

PD is characterized by the degeneration of DA neurons in the substantia nigra (SN) of the midbrain, leading to subsequent motor symptoms, such as rigidity, tremor, ataxia, and postural instability [30].
There are several mechanisms presumed responsible for the destruction of dopaminergic neurons in the SN: oxidative stress, neural inflammation, and mitochondrial dysfunction [31]. DA neurons are highly susceptible to damage in relation to high ROS levels [10]. Neural inflammation is evidenced in PD degeneration by the high levels of inflammatory cytokines. Activated microglial cells lead to dopaminergic cell death by phagocytosis and increased ROS production [32].
Brain RAS has been lately reported in influencing dopaminergic regulation, neurotransmission, and neuron survival [33].
A significantly higher level of Ang II in the CSF or brain tissues was observed in PD animal models, as well as patients with this disease. Ang II is secreted by glial cells (microglia, astrocytes, and oligodendrocytes) in regions responsible for cardiovascular functions and in other brain regions. It plays an important role in memory, anxiety, bipolar disorder, and PD [34]. The level of AT1R was also increased in the SN of PD rats and overactivation of the brain Ang II/AT1R axis contributed to the progression of PD [35]. Mitochondrial ATP-dependent potassium channels (KATP) induce dopaminergic neuronal loss, stimulate the superoxide-induced damage, and increase the inner mitochondrial membrane potential induced by Ang II administration. All these aspects can be stopped or at least reduced by inhibiting Ang II stimulation by ARBs [36].
The coupling of Ang II to AT1R leads to inflammation, increased ROS production, and activation of the NADPH complex. Its overactivation determines an increase in DA release, as well as neuroinflammatory and neurotoxic effects in the brain. The Ang II/AT1R axis has inhibitory effects on GABA and excitatory effects on glutamate. Thus, it is suggested that activating type 1 receptors plays an important role in motor deficits in PD through the indirect pathway of the SN [37]. Large studies suggest that using RAS inhibitors may be associated with a reduced risk of PD. However, a statistically significant risk reduction in PD incidence was observed after administration of ARBs, but not in the case of ACEI use  [38].
The neuroprotective effects due to the binding of Ang II to AT2R improve neural growth as well as cognitive processes, learning, memory. This is caused by activation of nitric oxide (NO) production [14]. Low levels of Ang II are linked to an increase in the severity of depressive symptoms [39].
AT1R has pro-apoptotic activity in DA neurons, either through oxidative stress mediated by NADPH or through apoptotic signaling of the mitochondria [35]. In the DA neurons of SN, Ang II enhances the expression of mRNA and AT1R protein, inducing their overactivation. AT1R activates a mitogen-activated protein kinase (MAPK) cascade initiated by the protein kinase C (PKC), which also activates the NADPH complex, the main source of ROS production in the cell [40].
Ang II/AT2R activation may be a pathway for a series of neuroprotective effects on cerebral tissue. AT2R increases NO production, stimulates neurite growth, and has beneficial effects on memory, learning, and cognition [14]. The Ang II/AT1R axis is responsible for the dopaminergic neuronal loss and reduction of 70% of tyrosine hydroxylase neurons restored with candesartan (Ang II-receptor inhibitor) and azilsartan in rotenone, 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (MPTP), and 6-hydroxydopamine (6−OHDA) PD mice models [35].

4. Renin-Angiotensin-Aldosterone System and Alzheimer’s Disease and Other Memory Disorders

AD is a neurodegenerative disorder characterized by abnormal changes, with progressively severe evolution leading to cognitive decline with memory loss. It is accompanied by behavioral disorders as well as functional deterioration of some organs [2][19][28].
Stress-inducers increase brain levels of Ang II, thus having an important role in AD. This hypothesis is supported by numerous studies that have reported that ARBs, such as losartan, olmesartan, candesartan, and valsartan, improved memory and other cognitive parameters; this has been observed in both animal models and patients with AD [19]. Ang II AT1 receptor blockers known as sartans have been recognized to have anti-inflammatory, neuroprotective, and neurorestorative effects in experimentally induced brain injury [41]. In a preclinical study conducted on primary cell cultures isolated from 8-day-old Sprague Dawley rat pups, the excitotoxicity of glutamate, a pathogenic factor in AD, and the effects of candesartan on glutamate were evaluated. This revealed that candesartan prevented glutamate-induced changes in gene expression, but its effects were not related to Ang II AT2 receptor stimulation because AT2Rs are not expressed in rat primary cerebellar granule cells (CGC) in vitro. The results argue for the inclusion of ARBs as a drug of choice for early cognitive impairment [42][43]. The anti-inflammatory effects of ARBs are due to the reduction in pro-inflammatory factors in the cerebral circulatory system, as well as the increase in cerebral flow that antagonizes neurodegeneration induced by cerebral ischemia [24].

5. Renin-Angiotensin-Aldosterone System and Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease of the CNS that affects both gray and white matter tracts, as well as the brain stem and basal ganglia [44][45].
Activated astrocytes by T-cells have a dual role during the development of the disease. They promote neurotoxicity in most areas where myelin sheaths are damaged, by secreting oxygen and nitrogen radical species, glutamate, and ATP [46]. Their local activation has a negative effect at major sites of progressive MS and leads to tissue destruction and neurological impairment [47]. They modulate BBB permeability and CNS inflammation due to the multifocal production and infiltration of cytokines [48][49].
The influence of RAS in microglial polarization is the consequence of two opposite effects. Thus, under pathological conditions, AT1R and AT2R are upregulated and activate microglia. The effects of nuclear AT1R that leads to pro-inflammatory/classically activated microglia (M1 substate) are counteracted by the opposite RAS arm represented by Ang II/AT2R that leads to anti-inflammatory/alternatively activated microglia (M2 substate) [10][50].
RAS is also spread in oligodendrocytes where it triggers opposite effects depending on the type of receptors. Whereas AT1R activation promotes demyelination, AT2Rs lead to a re-myelination process with positive consequences in MS pathology [51]. A study by Lee et al. pointed out the presence of higher anti-AT1R antibodies titers in MS patients compared with those with stable relapsing-remitting or progressive MS, thus being correlated with recent disease activity [52].
Another conclusive aspect represents the involvement of RAS in immune activity. Accumulated evidence has demonstrated that AT1 receptors are located on immune cells, such as macrophages, T-cells, natural killer (NK), or dendritic cells [53]
Modulation of RAS components may influence MS pathology through the modulation of the autoimmune response.

6. Renin-Angiotensin-Aldosterone System and Huntington’s Disease

HD, also termed Huntington’s chorea, is an autosomal dominant neurodegenerative disorder with a prevalence of 10.6–13.7 per 100,000 individuals in Western countries [54]. HD is caused by an abnormal expanded repeat of CAG trinucleotide in the huntingtin (HTT) gene, which leads to the formation of mutant huntingtin protein (mHTT), a key player in the pathogenesis of the disorder [54][55][56][57].
RAS is involved in different functions of the brain, including behavior, cognition, and motor control. It is linked to NDG diseases, with Ang II being considered a key component; it is involved in neuronal death through oxidative stress, inflammatory responses, and apoptosis [9]. These effects were confirmed in animal models of different NDG diseases, such as PD [58]. Thus, studying RAS may shed light on other NDG diseases, such as HD, allowing for alternative management strategies.
Studies have reported that the blockage of AT1 and AT2 receptors with compounds such as losartan and PD-123177, as well as ACE inhibition through the use of captopril, reduced oxidative stress in the hippocampus of rats, an effect that could be explained by the central inhibitory effect of Ang II. This could lead to a possible new therapeutic approach, considering that oxidative stress may play a role in the pathogenesis of HD. Another important finding was the association between higher levels of ACE2 and higher scores on tests that evaluate verbal fluency, suggesting that higher ACE2 levels are correlated with better verbal function [59][60].
De Mello et al. have shown that mHTT-expressing striatal cells are sensitive to Ang (1–7), with its effect being related to the MasR that can be found in areas such as the amygdala, hippocampus, forebrain, olfactory bulb, piriform cortex, thalamus, and portions of the hypothalamus. Studies have shown that patients with HD had reduced activity of ACE in brain regions specific to HD pathogenesis, such as the caudate nucleus, putamen, and globus pallidus. These findings suggest that the ACE/Ang II/AT1R axis is reduced in HD patients, whereas the ACE2/Ang (1–7)/MasR axis in mutant neurons is predominantly activated, suggesting the involvement of RAS in the pathogeny of HD [7].

7. Renin-Angiotensin-Aldosterone System and Motor Neuron Disease

MND is a generic name for several neurological pathological entities that progressively afflict motor neurons, reducing body motor abilities until invalidity and death. Specific symptoms include muscle atrophy, muscular spasms such as fasciculations, muscle spasticity, and/or hyperreflexia. The capability to walk, speak, swallow, or breathe is gradually lost.
Several years ago, Japanese [61][62] and Taiwanese [63] researchers coincidentally discovered that the administration of pharmacological treatments that modulate the RAS may induce a more favorable evolution of lateral amyotrophic sclerosis (LAS). According to them, the cerebrospinal concentration of Ang II is negatively correlated with the presence and degree of evolution of MND.
Among the theories suggested by various researchers, one was the possible protection of neural tissue through the AT2R, due to its antioxidant and cell proliferation-stimulating actions. Another theory was the reduction in the amount of Ang II from the cerebral tissue, which would reduce the deleterious effects of AT1R stimulation. These hypotheses have been correlated with similar effects seen in patients with AD or PD [64][65][66][67][68]. The enhancement of glial and neuronal inflammation mediated by the AT1R, accompanied by microgliosis and the added stimulation of oxidative stress by extracellular and intracellular Ang II have been linked to MND [69][70].
Another hypothesis was the direct augmentation of neural protection through vitamin E (α-tocopherol), a known liposoluble antioxidant [71] (Table 3).
The inhibition of the glutamatergic stimulation was one of the other presumptive mechanisms of the protection induced by ACE blockers in other NDG afflictions [72].
Studies using neuronal cell cultures demonstrated that Ang II, in the presence of aldosterone, another component of the same physiological system, may have a deleterious effect on neurons, with possible astrocytic involvement. Inhibition of the aldosterone receptor with eplerenone [73] reduced the damaging effect on the neurons more than AT1R inhibition by valsartan. The deduction obtained was that astrocytes, stimulated by Ang II, produced more aldosterone, which had a damaging effect on neurons in culture. This effect, in turn, was inhibited by the addition of eplerenone [74].

8. Renin-Angiotensin-Aldosterone System and Prion Disease

The term was coined by Prusiner in 1982 and means “proteinaceous infectious particles” [75][76]. These are NDG diseases induced by the natural transformation of a neuronal natural membrane protein called PrPC (cell prionic protein), a membrane glycoprotein that presents two helixes and two complex oligosaccharide chains coupled at the N-terminal head [77] [78].
This is a normal protein, abundantly present within the neuronal cell membrane, anchored by a GPI (glycosyl-phosphatidyl-inositol) anchor and aggregated in lipid rafts. It is encoded by the PRNP gene, located on chromosome 20 in humans and on other chromosomes in various animal species [77]. Besides neurons, it has also been identified in glial cells, immune cells, epithelial cells, or endothelial cells. Its major implications appear to be in cell survival, especially against free radical aggression and apoptosis, as well as in cell adhesion [79]. However, there are situations in which PrPC is internalized and metabolized in multiple ways, which seem to change its functions. Among the essential physiological functions of this protein are protection against apoptosis induced by lack of growth factors, protection against oxidative stress, and protection against endoplasmic reticulum stress, caused by the accumulation of misfolded/unfolded proteins in the endoplasmic reticulum [80].
PrPC frequently interacts with a multitude of neuronal proteins, including nicotinic cholinergic receptors. They control their postsynaptic activation, which could explain the cholinergic manifestations induced by PRD [81].
Also, there is a very well-documented interaction of PrPC with the τ proteins in AD and with α-synuclein, which could be responsible for some parkinsonian symptomatology in PRDs [82]. Similar to the evolution of PrPC towards PrPSc in PRDs such as kuru, Creutzfeldt-Jakob, GSS, and fatal familial insomnia, all NDG afflictions show misfolding proteins, such as α-synuclein [83], A-β, APP, τ in AD, TDP-43 in ALS, HTT, and the amyloid protein [84]. These have been labeled “prionoids” and some attempts to mimic the disease by transferring these proteins in cell cultures or animal models have been successful in inducing neurotoxicity [85][86].

9. Conclusions

There is strong evidence that dysregulation of brain RAS has an important role in BNDs. The exacerbation of neuroinflammation, which is considered a key factor in several brain disorders, such as AD, PD, or MS, is explained with AT1R activation through Ang II/AT1R signaling. Activation of the ACE2/Ang (1–7) neuronal axis/Mas R promotes neuroprotection via antioxidant and anti-inflammatory effects and could have great potential om the development of new therapeutic options for pathologies including PD, AD, MS, HD, MND, or PRD.

Abbreviations

3-NP 3-nitropropionic acid
6-OHDA 6-hydroxydopamine
Ach Acetylcholine
ATP Adenosine triphosphate
AD Alzheimer’s Disease
APP Amyloid precursor protein
A-β β-amyloid
Ang Angiotensin
ARB Angiotensin receptor blocker
ACE Angiotensin-converting enzyme
ACEI Angiotensin-converting enzyme inhibitor
Angt Angiotensinogen
ALS Lateral amyotrophic sclerosis
BBB Blood-brain barrier
BND Brain neurodegenerative disease
BK Bradykinin
PrPC Cell prionic protein
CNS Central nervous system
CGC Cerebellar granule cells
CSF Cerebrospinal fluid
CVD Cardiovascular diseases
CVO Circumventricular organ
C21 Compound 21
DAG Diacylglycerol
DMT Disease modifying treatment
DA Dopamine
EAE Experimental autoimmune encephalomyelitis
GSEA Gene-set enrichment analysis
GPI Glycosyl-phosphatidyl-inositol
HGF/c-Met Hepatic Growth Factor/tyrosine kinase type I receptor
HTT Huntingtin
HD Huntington’s Disease
IB Inclusion bodies
IP3 Inositol triphosphate
IRAP Insulin-regulated aminopeptidase
JG Juxtaglomerular
LAS Lateral amyotrophic sclerosis
MPTP Methyl-phenyl-tetrahydropyridine
KATP Mitochondrial ATP-dependent potassium channel
MAPK Mitogen-activated protein kinase
MND Motor Neuron Disease
MS Multiple Sclerosis
mHTT Mutant huntingtin protein
MOG Myelin oligodendrocyte glycoprotein
NK Natural killer
NDG Neurodegenerative
NADPH Nicotinamide adenine dinucleotide phosphate
NO Nitric oxide
NOS Nitric oxide synthase
NOX Nicotinamide adenine dinucleotide phosphate oxidase
NF-κB Nuclear factor-κB
PD Parkinson’s Disease
PPAR-γ Peroxisome proliferator-activated receptor-γ
PIP2 Phosphatidylinositol biphosphate
PRD Prion Disease
PRR Prorenin receptor
PKC Protein kinase C
PLP p139–151 Proteolipid protein 139–151 peptide
ROS Reactive oxygen species
R Receptor
RRMS Relapsing remitting MS
RAS Renin-angiotensin-aldosterone system
SG Stress granules
SPN Spiny projection neurons
SN Substantia nigra
SMN Survival motor neuron
TSP-1 Thrombospondin-1
TJ Tight junction
TGF-β Transforming growth factor-β
TNF-α Tumor necrosis factor-α
WT Wild-type
VEGF Vascular endothelial growth factor
Zn Zinc

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