Misregulation Of Wnt Signaling Pathways At The Plasma Membrane in Brain And Metabolic Diseases Part 2

3. Wnt Signaling at the Plasma Membrane in Aging and Brain Disorders

Synaptic plasticity and transmission are reduced in the aging brain [46,47]. Loss of synaptic contact is a major feature of Alzheimer's disease (AD), which is the most common cause of dementia [48]. 

Synaptic plasticity refers to the adjustability and changeability of the strength of synaptic connections. Synaptic plasticity is the basis of information transmission between important neurons in the brain and is also a key link in memory formation and memory enhancement.

Studies have shown that synaptic plasticity in the brain can be significantly enhanced through some means, such as learning, memory, exercise, and artistic performance. The strength of information transmission between synapses can be changed through the production and secretion of new neurotransmitters, as well as changes in the morphology and number of synapses.

This enhancement of synaptic plasticity is the key to our continuous improvement in memory ability. When we need to learn and remember some information, the synaptic plasticity in the brain will be activated, making it easier to store and quickly retrieve new information.

Through a lot of training and practice, we can further enhance the plasticity of synapses in the brain and further increase the ability to remember. Therefore, positive and active learning and training is a positive use of synaptic plasticity, which can enhance our memory ability and show more of our potential.

Therefore, we should actively learn, explore, and exercise ourselves to improve synaptic plasticity and memory ability. I believe that as long as we persevere and make continuous progress, we will be able to perform better in future studies and life. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of the neural network. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

Click know ways to improve brain function

Late-onset Alzheimer's is the most common form of the disease, and the decrease in synaptic strength is closely associated with the reduced susceptibility of synapses to toxic molecules such as Aß [46]. 

Wnt signaling is known to play essential roles in synapse formation, function, and maintenance in the adult brain [49]. The Wnt signaling pathway also appears to be associated with replicative cellular senescence and aging [46]. 

The fact that the Wnt signaling pathway is disturbed during aging suggests that Wnt signaling can enhance synaptic function during aging and improve AD-related synaptic pathology. 

Expression of the plasma membrane components Wnt2b, Wnt6, Wnt7a, Fz2, and Fz3 has been found to decrease with age, while that of Lrp6 and the Wnt antagonist secreted frizzled-associated protein 1 (Sfrp1) increase during aging. [50]. 

Moreover, there is a general decrease in Wnt signaling with age-especially in the lungs and the brain [51]. Interestingly, long-term loss of 17β-estradiol (E2 or estrogen) after menopause causes an elevation of neural Dickkopf-1 (Dkk1)-a secreted Wnt antagonist that binds to Lrp6-and a reduction in Wnt/β-catenin signaling activity, ultimately causing neurodegeneration [52]. 

Moreover, E2 has been shown to suppress Dkk1 and employ a neuroprotective effect. Thus, estrogen appears to prevent neurodegeneration through Wnt/β-catenin signaling activation. 

The dynamic alterations in plasma membrane domains are considered to be important for signal transduction in neurogenesis and, thus, contribute to aging and the development of brain diseases. 

A prominent work has supported this hypothesis by showing that enrichment of the (pro)renin receptor ATP6AP2 in caveolae/lipid raft microdomains is essential for neuronal differentiation of stem cells, with a concomitant transition from Wnt/β-catenin to Wnt/PCP signaling, and that these domains may be used as a potential target for the treatment of neurodegenerative disorders [53]. 

In a group of patients with neurodegenerative diseases, ATP6AP2-which is associated with membrane microdomains-has been reported to be regulated by intracellular Ca2+ and Gαq proteins, and to induce neuronal differentiation [53]. 

The glycoprotein M6a (GPM6a), which becomes localized to the lipid rafts and induces their clustering in a palmitoylation-dependent manner, likewise regulates neuronal polarity and accelerates neuronal differentiation [54]. 

Palmitoylated membrane proteins generally prefer to concentrate in lipid rafts [55–57]. Since GPM6a is one of the major palmitoylated proteins in the adult brain, it is likely that the lipid rafts play key roles in brain functions, and are associated with brain diseases including AD, PD, SZ, and Huntington's disease [54,58]. 

Under this section, we will review the dysregulation of the Wnt signaling pathway at the plasma membrane and its domains in the common brain disorders AD, PD, and SZ.

3.1. Alzheimer's Disease

Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for two-thirds of dementia cases [59–61]; it is defined as an irreversible and progressive brain dysfunction, and characterized by deterioration or loss of cognitive functions such as memory and thinking and, at the most advanced stage, of the ability to carry out daily tasks. 

The pathology of the disease is characterized by the accumulation of certain proteins, inflammatory changes, and neuronal cell death [48]. The extra- and intracellular accumulation of amyloid beta (Aβ) plaques and hyperphosphorylated Tau protein correlate strongly with cognitive impairment [60,62]. 

In addition, loss of synapses is observed in the early stages of AD progression, while neuronal cell death is observed in the late stage [63,64]. The secreted Wnt antagonist Dkk1 was found to be highly expressed in the brains of Alzheimer's patients and murine AD models [65,66]. 

In parallel, increased Gsk3ß activity, reduced cytoplasmic ß-catenin levels, and low Wnt signaling activity were detected in the brains of AD patients [67–71]. Mass spectrometric analysis of samples obtained from patients' brains also validates the decrease and deterioration in canonical Wnt signaling [72–74]. 

Aß accumulation in the hippocampal neurons is known to reduce canonical Wnt activity and enhance synaptic loss by increasing Dkk1 expression [75]. Inhibition of Dkk1 by neutralizing antibodies has been found to completely abolish the Aß effect on synapses and prevent synaptic loss [76]. 

In a transgenic murine model that expresses Dkk1 in the brain in an inducible manner, Dkk1 was found to cause synapse and memory deficits in the striatum and hippocampus, decrease in long-term potentiation (LTP), and increase in long-term depression (LTD), without affecting cell viability [77,78]. 

Moreover, postnatal deletion of Lrp6 from forebrain neurons in a murine model of AD triggered amyloidogenesis of APP, leading to synaptic loss and exacerbating AD pathology [79]. 

Dkk1 also acts as an activator of non-canonical Wnt–PCP signaling and, hence, promotes synapse withdrawal and further Aβ production [73]. Genetic variants of Lrp6 have been investigated for being a risk factor for late-onset AD. For example, the Ile-1062-Val variant (exon 14) of Lrp6, which reduces the activity of Wnt/βcatenin signaling, appears to be a genetic risk factor for AD [68]. 

Moreover, silencing of long non-coding RNA (lncRNA) SOX21-AS1, which targets FZD3/5 genes, causes activation of the Wnt/β-catenin pathway, reduces neuronal oxidative stress, and suppresses neuronal apoptosis in mice with AD [80]. 

Activation of canonical Wnt signaling is known to protect the hippocampal neurons against the neurotoxicity of Aβ peptides [46]. The canonical pathway ligand Wnt3a and receptor Fzd-1 inhibit Aβ toxicity by activating the Wnt/βcatenin pathway [81,82]. 

In conclusion, activation of the Wnt/β-catenin pathway reduces Aβ formation and neural toxicity, leading to synapse activation. In addition to the protein components of the Wnt pathways, the lipid membrane microenvironment also plays a key role in AD. 

For example, cholesterol content and distribution are associated with Aβ production and cell dysfunction in AD [20]. Aβ appears to accumulate in the lipid rafts, which act as the primary mediators of the relevant oxidative stress at the plasma membrane [83]. 

Amyloid peptides tend to bind to the membranes specifically within the ordered domains enriched in cholesterol [84–87]. Moreover, Aβ was found to bind to the sphingolipid GM1 gangliosides (GM1/Aβ) in the brains of patients who exhibit early pathological features of AD, suggesting that GM1/Aβ may promote amyloid toxicity [88]. 

This binding of Aβ to the plasma membrane has also been found to be facilitated by the cholesterol content of the membrane, by altering the binding capacity [89]. 

Clustering of GM1 appears to be strongly enhanced by another sphingolipid, sphingomyelin-particularly at the neuritic terminals [90]. These findings correlate with the significantly increased SM levels in the membrane microdomains and synaptosomes that are isolated from aged murine brains [91]. 

In contrast, more recent work has demonstrated that while sphingomyelin triggered oligomerization of Aβ monomers, physiological levels of GM1 did not [92]. 

Thus, decreasing levels of GM1 in the brain can reduce protection against Aβ oligomerization and contribute to the onset of AD. In this case, the oligomerization-promoting action of GM1 can be explained by the extreme and non-physiological experimental conditions [92]. 

Thus, the influence of GM1 along with other sphingolipids in Aβ accumulation deserves to be further explored. Since regulation of the Wnt pathway has been widely associated with the ordered domains of the plasma membrane, it is essential to investigate the influence of changes in the membrane lipid environment on amyloidogenesis via affecting Wnt signaling activity. 

This would unravel yet-unknown mechanisms of Wnt signaling in AD progression, and propose potential new therapeutic approaches. Although Aβ accumulation and abnormal Tau protein accumulation are the most widely accepted mechanisms for AD, they are insufficient to explain the disease mechanism and to target AD therapeutically [60,61]. 

For example, in clinical studies conducted to date, reducing Aβ alone has not given promising results. Cholinergic neurotransmission in the cerebral cortex and basal forebrain has been shown to play an important role in the development of AD, proposing the cholinergic system as a main focus in the treatment of the disease [93]. 

Nicotinic acetylcholine receptors (nAChRs)-the ligand-gated ion channels that respond to the neurotransmitter acetylcholine-reside and cluster in the lipid rafts and interact with lipids surrounding the transmembrane domain [20,94]. 

The changes in levels of cholesterol and sphingomyelin at the plasma membrane can alter the localization and function of the nAChRs. Disruption of lipid rafts in rat primary hippocampal neurons by targeting the levels of cholesterol and sphingomyelin results in significant changes in nAChRs [95]. 

Moreover, again-a proteoglycan that acts at the neuromuscular junction- mediates AChR clustering in the lipid rafts, causing further partitioning of the muscle-specific receptor tyrosine kinase (MuSK) into lipid rafts [94]. 

Lipid rafts are necessary for MuSK activation and downstream signaling. Interestingly, AChR clustering is mediated by rapsyn-an intracellular protein that constitutively becomes localized to the lipid rafts, and is dependent on the rafts to interact with the AChR [94]. 

These studies reveal that lipid rafts considerably affect the function of the nAChRs, which have been shown to play a crucial role in AD development, and further point to the importance of lipid rafts in the development of therapeutic approaches for AD.

3.2. Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disease, following AD, with an age-dependent prevalence of 1-4% [96–98]. PD is a sporadic or familial inherited disease with complex symptoms that include resting tremors, bradykinesia, increasing muscle tension, and postural instability [96,97]. 

PD is characterized at the molecular level by loss of dopaminergic neurons in the substantia nigra-a region in the midbrain-and accumulation of ubiquitin- and α-synuclein (aSYN)-positive cytoplasmic inclusions called Lewy bodies (LBs) [99,100]. 

Mitochondrial dysfunction, protein misfolding and aggregation, oxidative stress, immunity inflammation, autophagy, and apoptosis have been shown to contribute to neurodegeneration in PD [101]. 

Glutamate excitotoxicity also plays a role in the pathogenesis of PD, and excitatory amino acid transporters (EAATs) are important in removing glutamate [102]. 

The Wnt signaling pathway has been reported to exert a protective effect against PD by inducing the expression of EAATs [103]. 6-Hydroxydopamine treatment promoted cell death in astrocytes and dopaminergic cells, and inhibited expression of Wnt1, β-catenin, and EAAT2; on the other hand, Wnt1 overexpression decreased glutamate levels, and upregulated β-catenin, EAAT2, and nuclear factor kappa-B (NF-κB) levels [103]. 

Thus, by promoting EAAT2 expression, Wnt1 could inhibit dopaminergic neuron loss and play a cytoprotective role in PD. 

The pesticides paraquat and maneb, which interfere with mitochondrial function and cause toxicity via oxidative stress, have been shown to cause neurotoxicity in the dopaminergic system and, thus, increase the risk of PD [104,105]. 

Both toxins decrease the expression of Wnt1 at the protein and mRNA levels in rats, while increasing the expression of Wnt5a, which induces the differentiation of neural cells into dopaminergic precursors and increases the proliferation of progenitor cells [106]. 

Moreover, miR-34-b/c, which was found to be downregulated in brain areas of PD patients before the appearance of motor dysfunction, silences expression of Wnt1 by targeting it at the 3'UTR and enhances differentiation of murine embryonic stem cells or transdifferentiation of fibroblasts into dopaminergic neurons [107,108]. 

In contrast, Wnt4 overexpression in a Drosophila model of PD has been found to significantly reduce disease-related abnormalities, such as impaired flight ability, by inhibiting autophagy and apoptosis and restoring mitochondrial function [109]. These data, taken together, suggest that different Wnt ligands could play opposing roles-i.e., offensive or protective-in the course of PD [109]. 

Properties of the membrane lipid environment can affect the prognosis of PD. The familial PD-linked proteins α-synuclein, LRRK2, parkin, and DJ-1 have been demonstrated to be associated with the lipid rafts, strongly suggesting that lipid rafts are involved in the pathogenesis of PD [110,111]. 

E3 ubiquitin ligase tumor necrosis factor-receptor associated factor 6 (TRAF6)-which binds to and ubiquitinates mutant DJ-1 and aSYN proteins, stimulates the aggregation of these insoluble and polyubiquitinated forms as LBs in PD [112]. 

Colocalization of TRAF6 with aSYN in LBs in postmortem brains of PD patients highlights the importance of atypical ubiquitination in the pathogenesis of PD. Strikingly, the majority of the endogenous TRAF proteins were detected in the lipid raft fractions, and this was controlled by the RANK ligand-the receptor activator of the NF-κB ligand [113]. 

Furthermore, GM1 levels have been found to increase in some neuronal populations in PD, and elevated GM1 levels are associated with increased toxicity of misfolded protein oligomers [114]. 

aSYN directly associates with the ganglioside GM1, which is highly abundant in the lipid rafts, and results in the elimination of aSYN fibrillation by supporting its internalization [115]. 

Thus, there is growing evidence that both Wnt signaling and plasma membrane domains are associated with the pathogenesis of PD. However, the potential link between Wnt signaling and PD through membrane domains remains to be investigated. 

It would be very interesting to test the potential of membrane microdomains as therapeutic targets in PD.

For more information:1950477648nn@gmail.com