A Review Of The Common Neurodegenerative Disorders: Current Therapeutic Approaches And The Potential Role Of Nanotherapeutics Part 1

Abstract: 

Neurodegenerative disorders are primarily characterized by neuron loss. The most common neurodegenerative disorders include Alzheimer's and Parkinson's disease. 

Neurodegenerative disease is a disease that seriously affects the physical and mental health of the elderly. Its main manifestations are the gradual decline of brain function and memory loss. Although neurodegenerative disease is a very terrible disease, we should not be obsessed with its negative effects, but should actively explore how to prevent and treat this disease.

The relationship between memory and neurodegenerative disease is very close. Once a neurodegenerative disease occurs, the patient's brain will be damaged to varying degrees. This damage will not only affect the patient's physical health but also affect the patient's cognitive ability and memory. Therefore, protecting brain health is our top priority in fighting neurodegenerative diseases.

So, how to protect brain health? Here are a few suggestions:

1. Keep exercising: Proper exercise can promote blood circulation, enhance the body's immunity and endurance, help slow down the development of neurodegenerative diseases, and reduce the risk of illness.

2. Maintain a healthy diet: Eating healthy food can provide the brain with sufficient nutrition, which helps slow down the development of neurodegenerative diseases. Pay attention to the intake of fat and sugar in the diet and avoid overeating.

3. Maintain social activities: Regular participation in social activities can promote brain activity and help slow the development of neurodegenerative diseases.

4. Active learning: Maintaining enthusiasm for learning can stimulate the vitality of the brain and help slow the development of neurodegenerative diseases.

In short, we should face neurodegenerative diseases positively instead of indulging in their negative effects. Only by maintaining a positive attitude can we effectively prevent and treat neurodegenerative diseases and keep our brains healthy and full of vitality. It can be seen that we need to improve memory. Cistanche can significantly improve memory because Cistanche 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 neural networks. 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 Short-term Memory how to improve

Although there are several medicines currently approved for managing neurodegenerative disorders, a large majority of them only help with associated symptoms. 

This lack of pathogenesis-targeting therapies is primarily due to the restrictive effects of the blood-brain barrier (BBB), which keeps close to 99% of all "foreign substances" out of the brain. 

Since their discovery, nanoparticles have been successfully used for targeted delivery into many organs, including the brain. This review briefly describes the pathophysiology of Alzheimer's, Parkinson's disease, and amyotrophic lateral sclerosis, and their current management approaches. 

We then highlight the major challenges of brain-drug delivery, followed by the role of nanotherapeutics in the diagnosis and treatment of various neurological disorders.

Keywords: nanoparticle; neurodegenerative disorder; neurogenesis; Alzheimer's disease; Parkinson's disease; blood-brain barrier; amyotrophic lateral sclerosis.

1. Introduction

Neurodegeneration has been identified as the pivotal pathophysiological change in most brain-related disorders [1]. Regardless of the incessant efforts by modern science to create a medical or surgical solution, the outcome has not been favorable. 

Neurodegenerative disorders (NDs) such as Alzheimer's and dementia continue to be a clinical concern in most older people [2,3]. The highly effective blood-brain barrier (BBB) continues to be a real barrier to the successful management of NDs. 

Despite the several successes that have been demonstrated with surgeries and highly evasive techniques, their clinical acceptance is limited due to varying concerns about their long-term benefit, owing to the potential damage to the brain barrier. 

As a suitable alternative for halting or reversing neurodegeneration, nanotherapeutics with the potential to cross the BBB (without damage to the barrier) have been proposed and demonstrated in many cases [4,5]. Nanotherapeutic use is gaining traction due to the several benefits compared to conventional dosage forms [6]. 

Despite this great progress, there is a need to refine nanotherapeutics to ensure optimum outcomes. In this review, we initially describe the pathophysiology of major NDs and their current management strategies. 

We also discuss the role of BBB and other challenges for brain-targeted drug delivery. Further, we look at the potential role of nanotherapeutics in the fight against neurodegeneration. Finally, we discuss breakthroughs and current findings in nanotherapeutics to manage NDs and provide perspectives for future applications.

2. Neurodegenerative Disorders (NDs)

Neurons are central to the proper functioning of the human brain since they play a critical role in communication [7,8]. Most neurons originate in the brain; however, neurons are present everywhere in the body [9,10]. 

During childhood, neural stem cells produce the majority of neurons, the number of which is significantly reduced in adulthood [11]. Although neurons are not immortal, the progressive loss of neurons, neuron structure, and/or their functions, known as neurodegeneration, is central to the pathophysiology of several brain disorders [12] and is also a major health concern. 

Neurodegeneration is associated with dysfunction of the synapse, and neural network, and the deposition of physiochemically altered variants of proteins in the brain (Figure 1) [13–16]. 

Diseases with neurodegeneration as their hallmark feature are collectively termed NDs [17,18]. The most common NDs include Alzheimer's disease, Parkinson's disease, prion disease, Amyotrophic lateral sclerosis, motor neuron disease, Huntington's disease, spinal muscular atrophy, and spinocerebellar ataxia [17,19–21].

Figure 1. Path to cognitive decline in neurodegeneration. Amyloid-beta (Aβ) monomers clump together to form oligomers of variant structures. Subsequently, the oligomers aggregate to form Aβ fibers, which misarrange to form Aβ plaques. Plaque formation induces an inflammatory response Figure 1. Path to cognitive decline in neurodegeneration. 

Amyloid-beta (Aβ) monomers clump together to form oligomers of variant structures. Subsequently, the oligomers aggregate to form Aβ fibers, which misarrange to form Aβ plaques. 

Plaque formation induces an inflammatory response which includes the formation of tau aggregates leading to the conversion of healthy neurons to diseased neurons. 

The presence of more diseased neurons triggers another inflammatory response leading to more neuron loss and a subsequent loss in brain function as well as cognitive decline.

Neurodegenerative disorders affect millions of people worldwide. Although age is the single most contributing risk factor to the development of all NDs, recent findings reveal that a combination of an individual's genetic makeup and environmental factors can equally contribute to increasing the risk for NDs. Further, despite the expression of specific genes (within an individual) accountable for NDs [22], the time and extent of neurodegeneration largely depend on their immediate environment [23,24]. 

More recent studies reveal that multiple pathologies may underline a single neurodegenerative disorder [25–28]. Thus, NDs can be very serious or even, in certain instances, life-threatening; however, it solely depends on the type and stage of the disease. 

Since the brain controls several aspects of the body's function, neurodegenerative diseases consequently affect multiple facets of human functioning and limit the ability to perform both basic (e.g., speech, movement, stability, and balance) and complicated tasks (e.g., bladder and bowel functions, and cognitive abilities). 

Most NDs progress without remission, whilst in some cases, treatments target the improvement of symptoms, relief of pain if present, and/or the restoration of balance and mobility. In the following sections, we will briefly discuss some common NDs.

2.1. Alzheimer's Disease (AD)

More recent studies of Alzheimer's disease pathophysiology have shown that the accumulation of amyloid-beta (Aβ) and tau proteins is central to AD progression [29,30]. 

The formation of Aβ-containing plaques within the brain, linked with neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, has been identified as the classical feature of AD [31–33]. 

Plaque formation disrupts hippocampal circuitry leading to poor short-term memory consolidation into long-term traces [34]. In AD, there is extensive neuronal loss, faulty synaptic connections, and damage to the essential neurotransmitter systems necessary for brain functions, including memory. Thus, the most common clinical symptom in early-stage AD is selective memory impairment. 

In addition, hippocampus and medial temporal-lobe-dependent functions, such as declarative episodic memory, are also often affected. Finally, executive function impairment, judgment, and problem-solving are additional clinical manifestations and usually appear early [35].

2.2. Parkinson's Disease (PD)

Parkinson's disease is a progressive neurological disorder that leads to tremors, muscle stiffness, unsteady walking, and balance and coordination difficulties. Both genetic and non-genetic stimuli cause PD. 

Age is considered the primary risk factor for PD [36,37]. In addition, several other factors, such as excessive caffeine intake, smoking, and exposure to environmental toxins, are known to modulate the risk of development of PD [38], although the exact mechanism remains unclear [39–41]. The pathophysiology of PD primarily includes frontal cortex atrophy and ventricular enlargement. 

However, the most distinctive morphological alteration observed in the PD brain is the loss of pigmentation in the locus coeruleus and substantia nigra pars compacta (SNpc), which stems from the death of dopaminergic (DA) neuromelanin-containing neurons [42]. 

In PD, this significant cell loss results in dysfunction of the nigrostriatal pathway, culminating in decreased dopamine concentration within the striatum, and consequently, the cardinal motor symptoms [42]. 

Cell loss in different regions, including the nucleus basalis of Meynert, the raphe nuclei, the locus coeruleus, the pedunculopontine nucleus, the dorsal motor nucleus of the vagus nerve, the hypothalamus, and the olfactory bulb, account for the non-motor symptoms of PD [43]. 

Several mechanisms have been identified to play key roles in PD disease progression, and these include α-synuclein misfolding and aggregation, mitochondrial dysfunction, dysfunctional protein clearance systems, the ubiquitin-proteasome system, and autophagy-lysosome system, and neuroinflammation [37,42,44]. 

Microscopically, the presence of Lewy bodies (abnormal cytoplasmic deposits that are immunoreactive for the protein α-synuclein) within neuronal cell bodies, accompanied by dystrophic neurites (Lewy neurites), characterize PD [36,45]. 

Lewy bodies may be phosphorylated and spread to other regions of the CNS. Similar to AD, protein misfolding also occurs in PD [45], and the protein that is commonly misfolded is the tau protein. The abnormal hyperphosphorylation of tau protein leads to NFT formation. In a subgroup of PD patients, there are widespread plaques of NFTs and amyloid-beta plaques [46].

2.3. Amyotrophic Lateral Sclerosis (ALS)

ALS, more commonly referred to as motor neuron disease or Lou Gehrig's disease, is a progressive disease of the nerve cells and spinal cord, resulting in muscle weakness and paralysis [47,48]. In ALS, motor neurons gradually deteriorate before they die [49]. 

When motor neurons are damaged or dead, signals that should be sent to the brain are no longer delivered. Although over 30 different genes have been associated with ALS, mutations in four main genes (C9orf72, TARDBP, SOD1, and FUS) account for more than 70% of ALS cases [49]. 

These four genes encode proteins involved in major motor function aspects such as DNA repair, homeostasis, mitochondrial function, and glial cell function. A combination of these impaired functions is believed to contribute to the degeneration of motor neurons observed in ALS. Accumulation of intraneuronal protein aggregates is the pathological hallmark of ALS. 

The most abundant protein observed in most ALS patients is the TAR DNA binding protein; however, other proteins such as superoxide dismutase-1 and neurofilament can also form aggregates [50,51]. Nonetheless, it is unclear whether protein aggregates or protein complexes precede neuron damage or vice versa.

3. Current Therapeutic Approaches to Treat ND

Management of neurodegenerative disorders is often disease-specific. Several approaches to management are currently accepted, which either target the disease pathogenesis or attempt to improve the symptoms experienced. In this review, we consider the therapeutic approaches currently in practice to treat major NDs (Table 1).

3.1. Therapeutic Approaches for AD

Therapeutic approaches for managing AD focus mainly on targeting different pathways for disease progression. Currently, there are three classes of drugs approved by the US FDA for the management of AD, each of which is described below.

3.1.1. Antibody Targeting Amyloid-Beta (Aβ) Plaques

Aducanumab (Aduhelm) is the first disease-modifying drug approved for AD patients and was approved in June 2021 [52]. It is administered as an intravenous (IV) infusion over approximately one hour every four weeks. 

Aducanumab is an IgG1 monoclonal antibody specific to extracellular Aβ plaques in the brain, which binds and helps in clearing the plaques [52,53]. Although conditionally approved, clinical data on aducanumab show a reduction in the Aβ plaques' load, but with no relationship to improved cognitive function in patients. 

More clinical data will still be collected to provide conclusive evidence of whether the drug helps in cognitive functions. However, the approval of aducanumab has also created a wave of excitement in AD patients and advocacy groups. Besides being the first therapy to target altering the pathology of the disease, they believe it will create avenues for similar therapies shortly. 

Multiple clinical trials have been performed using different bioactive molecules (i.e., secretase inhibitors and therapeutic antibodies), but most of them have terminated so far. Some Aβ targeting antibodies-AAB-003, MEDI1814, RO7126209, and SAR228810- have completed clinical trial phase I. While aducanumab has completed clinical trial phase III, it is also specific towards Aβ aggregation. 

Similarly, tau or TREM 2 specific antibodies, i.e., BIIB076, bepranemab, JNJ-63733657, have completed clinical trial phase I, while gosuranemab is in clinical trial phase 2 [54]. Thus, additional antibody-based targeting medicine may obtain FDA approval for AD treatment shortly.

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