Alternative Targets To Fight Alzheimer’s Disease: Focus On Astrocytes Part 1

Abstract: 

The available treatments for patients affected by Alzheimer's disease (AD) are not curative. Numerous clinical trials have failed during the past decades. Therefore, scientists need to explore new avenues to tackle this disease. 

Alzheimer's disease is a neurodegenerative disease that is closely related to memory and usually occurs in the elderly. The disease causes the patient's brain to gradually shrink and lose many important neurological functions, including memory, thinking, language, and control of body movements. When patients lose a large number of nerve cells, they may find that their memory begins to have problems, which is also one of the most obvious and worrying symptoms for many Alzheimer's patients.

Although Alzheimer's disease causes a gradual memory decline, we should pay attention to the fact that Alzheimer's disease does not equal memory loss. Early diagnosis and treatment can significantly alleviate the disease and allow patients to maintain a relatively healthy and happy life. Compared with conventional treatment, drug treatment has a significant effect in alleviating symptoms and delaying the disease. In addition, auxiliary treatments such as physical therapy and speech therapy can also be used to help patients maintain optimal physical and mental state.

In addition, there are many measures that the patient's family and caregivers can take to help patients maintain a normal daily life. For example, developing a regular daily plan, following a regular diet, participating in social activities, etc., can all help patients slow the progression of the disease and maintain cognitive and behavioral autonomy. In addition, the company and support of relatives and friends can also have a positive impact on patients, making them more optimistic.

In short, although Alzheimer's disease will hurt patients' memory, active treatment and care can help patients maintain relative health and happiness. I believe that as long as our whole society pays attention and supports, we can bring a better life to all patients. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because Cistanche is a traditional Chinese medicine with many unique effects, one of which is to improve memory. The efficacy of Cistanche comes from the various active ingredients it contains, including tannic acid, polysaccharides, flavonoid glycosides, etc. These ingredients can promote brain health in many ways.

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In the present review, we briefly summarize the pathological mechanisms of AD known so far, based on which different therapeutic tools have been designed. Then, we focus on a specific approach that is targeting astrocytes. Indeed, these non-neuronal brain cells respond to any insult, injury, or disease of the brain, including AD. 

The study of astrocytes is complicated by the fact that they exert a plethora of homeostatic functions, and their disease-induced changes could be context-, time-, and disease-specific. However, this complex but fervent area of research has produced a large amount of data targeting different astrocytic functions using pharmacological approaches. 

Here, we review the most recent literature findings that have been published in the last five years to stimulate new hypotheses and ideas to work on, highlighting the peculiar ability of palmitoylethanolamide to modulate astrocytes according to their morpho-functional state, which ultimately suggests a possible potential disease-modifying therapeutic approach for AD.

Keywords: Alzheimer's disease; astrocytes; astrogliosis; beta-amyloid; neuroinflammation; neuroprotection; reactive gliosis; palmitoylethanolamide.

1. Introduction

Aducanumab, a monoclonal antibody directed against the aggregated form of the beta-amyloid peptide (Aβ), was the last unfruitful attempt to treat Alzheimer's disease (AD). 

At the beginning of November 2020, experts of the Peripheral and Central Nervous System Drugs Advisory Committee of the Food and Drug Administration expressed some concerns about the real efficacy of aducanumab, thus hindering its marketing claim [1]. 

The AD field had high expectations for the aducanumab clinical trials, primarily because this human IgG1 monoclonal antibody was designed to selectively bind Aβ aggregates, including soluble oligomers and insoluble fibrils but not monomers [2], suggesting the possibility to overcome previously failed approaches of other anti-Aβ antibodies. 

Unfortunately, the aims were never met, despite they had been well demonstrated at the preclinical level and in the early stages of the clinical trial. This event reveals once again the limitations of both basic and medical research anxiously focused on counteracting Aβ in AD [3]. 

AD is the most common form of dementia in the elderly, affecting about 47 million people worldwide [4]. Most AD cases are sporadic, affecting people older than 65 years old, and aging represents the greatest risk factor [5]. 

As life expectancy increases, it is reasonable to foresee that the number of AD patients will grow in the next decades. However, other risk factors have been identified besides old age. 

Growing epidemiological data support the existence of a link between metabolic disorders and AD [6–10], and a correlation between head injury and future risk of dementia has also been suggested. The risk of developing AD or vascular dementia is increased in many pathological conditions of the heart and blood vessels, including heart failure, diabetes, stroke, high blood pressure, and high cholesterol levels [11]. 

Family history and heredity are the most important risk factors for the genetic form of this disease, which affects about 1% of individuals with AD, and whose symptoms appear as early as 35 years old [12]. 

In contrast to heredity and aging, which are nonmodifiable factors, other risk factors could be controlled through general lifestyle improvement and effective management of unhealthy conditions. Indeed, healthy aging, which includes both physical and mental exercise, a balanced diet, staying socially active, and avoiding smoking, preserves both body and brain wellness and reduces the risk of developing dementia [13–15]. 

At a molecular level, the presence of two peculiar hallmarks characterizes the AD brain: (I) senile plaques, formed by the deposition of Aβ peptides in the extracellular space, and (II) neurofibrillary tangles (NFTs), due to the hyperphosphorylation of microtubule-associated tau proteins. 

A growing body of evidence indicates, however, that senile plaques and NFTs alone are not responsible for the cognitive impairments observed in AD [16]. Neuroinflammation and abnormal astrocytic and microglia responses exert a pivotal role in AD pathogenesis and progression, thus highlighting the complexity of this pathology [17–19]. 

AD can be considered as a continuum that spans decades [20], with brain modifications that begin 10–20 years before the clinical manifestations and change throughout the disease progression [21]. 

Various clinical stages have been classified, such as asymptomatic preclinical, prodromal, mild, moderate, and severe AD [22,23], also referred to as stage 1 to stage 6 [24,25]. 

Each stage is characterized by peculiar molecular changes that could represent possible targets for different therapeutic approaches [26–28]. AD is a neurodegenerative disease that impacts memory and cognition. In addition to the progressive impairment in mental abilities, other debilitating noncognitive symptoms usually appear, including sleep disturbances, loss of appetite, and neuropsychiatric conditions, including depression and/or apathy [29,30]. 

In the latest stages, symptoms worsen enough to interfere with daily activities such that people suffering from AD need continuous care. As a result, the economic burden of AD is impressive, mainly because currently approved drugs are not curative. 

Despite decades of intense research, no treatments are available to halt, slow, or cure AD, and the therapy still relies on cholinesterase inhibitors (donepezil, rivastigmine, and galantamine), and the N-methyl-D-aspartate (NMDA) antagonist memantine. 

Any of these drugs slightly help to manage behavioral symptoms, preserve mental skills, and slow down the disease progression. However, their effects are reversible and lessen over time due to the continued progression of the disease [31,32]. A final and confirmed diagnosis of AD can only be made through postmortem identification of histopathological hallmarks. 

Whenever a patient is suspected to have AD, he/she is already in a mild or moderate stage of the pathology, and substantial irreversible neuronal dysfunction and loss have already occurred. Nowadays, clinicians concur that intervening at the earliest stage of the disease could lead to a better outcome [22,33]. 

To do so, it will be necessary to identify biological markers allowing diagnosis in the asymptomatic (or, at most, prodromal) stage of the disease to recognize asymptomatic at-risk individuals and refer them to the use of disease-modifying drugs. 

This approach could be insidious and difficult to achieve since it falls into the field of preventive care. Despite the preclinical stage of AD could represent a temporal window in which it may be possible to reduce the incidence and progression of the disease [34], few preclinical data are available so far at this stage of the pathology [35]. 

To develop preventive therapeutic approaches for AD in the coming years, the key neurobiological mechanisms of AD need to be clarified. In this review, we discuss the most recent findings on both old and new mechanisms implicated in AD, with a particular reference to the role played by glial cells. The brain homeostatic functions exerted by the glia could represent a novel perspective in AD management, offering new strategies to treat this disease.

2. Old and New Pathophysiological Mechanisms in AD

2.1. The Amyloid Cascade Hypothesis

The correlation between Aβ deposition and dementia has extensively been studied during the past decades, and the amyloidogenic pathway has been widely investigated as a target for drug development [36]. Alois Alzheimer himself described the presence of plaques during the histological examination of his patient's-named Augustine- brain [37,38]. 

Later after, such plaques were recognized to be protein deposits, mainly Aβ peptides [39,40]. Several forms of Aβ peptides have been found in AD brains [41,42]. Longitudinal PET studies demonstrated that proteins begin to deposit about two decades before the first symptoms appear [43]; thus, plaque formation is a slow and prolonged process. 

Plaques accumulate extensively throughout the cortex, with the occipital and temporal lobes being the most affected [44]. Aβ peptides are generated by the cleavage of the type I transmembrane amyloid precursor protein (APP), a protein expressed ubiquitously, whose biological functions remain unclear [45,46]. APP is particularly abundant in the brain, and evidence shows that it has trophic properties [47]. 

It plays a role in brain development by promoting neural stem cell (NSC) proliferation, cell differentiation, and neuronal maturation [46,48]. APP seems necessary for synaptogenesis, synapse remodeling, and neurite outgrowth [49,50], as well as axonal outgrowth after injury in the adult brain [51]. 

A neurodegenerative role for brain APP has been hypothesized, even if the molecular mechanisms have not been elucidated yet. The production of APP increases in some physiological conditions, such as during neuronal maturation and differentiation, and in some pathological ones, including AD, brain trauma, and Down syndrome [52]. 

To complicate the picture, alternative transcriptional splicing could create 8 to 11 different APP isoforms [53]. The enzymatic processing of APP yields various peptides with distinct functions through three different proteolytic pathways, among which only one seems to be amyloidogenic. 

This process releases mainly two monomers of Aβ: about 90% is Aβ40, which is considered nontoxic because it does not self-aggregate much, and the remaining part is mainly constituted of longer Aβ peptides [54]. 

Being more hydrophobic and prone to aggregate than the shorter isoforms, the Aβ42 and Aβ43 could form oligomers and fibrils; thus, they are considered neurotoxic isoforms [36,55]. In addition to Aβ42 and Aβ43, some reports consider also the amyloid precursor protein intracellular domain to be involved in the pathophysiology of AD [52,56,57]. 

The nonamyloidogenic pathway is thought not to generate toxic Aβ and a third proteolytic pathway has been recently described, involving a η-secretase that cuts the APP extracellular domain releasing a soluble ectodomain. 

The biological functions of all peptides yielded through this newly described pathway are yet to be disclosed. Although most of the research studies investigated the neurotoxicity of Aβ peptides, they also exert biological functions. 

They are not abundantly expressed, even in AD brains [58], and they execute trophic actions, including cell fate specification and proliferation. Exogenous application of soluble and fibrillary Aβ peptides (but not oligomeric forms) stimulates human embryonic stem cell (ESC) proliferation [59]. Oligomeric Aβ peptides reduce the proliferative potential of human NSC, promoting their differentiation toward glial instead of neuronal cells [60]. 

The Aβ40 seems to preferably enhance neurogenesis, whereas the Aβ42 seems to promote gliogenesis [61,62]. Some authors have also observed neurogenesis induced by oligomers of Aβ42, and not Aβ40, in rat hippocampal NSCs [63]. Further studies are warranted since these contradictory results are probably due to the different forms of Aβ used. 

The amyloid cascade hypothesis states that the progressive accumulation and oligomerization of Aβ42 creates diffuse plaques in the brain parenchyma, causing neuroinflammation and, later, neurofibrillary tangles, ultimately leading to synaptic dysfunction or loss, and neuronal death [36,64]. 

This hypothesis has been formulated after having identified the APP gene on chromosome 21, together with the observation that people affected by Down syndrome develop AD-like symptoms early in life. Several pathogenic coding mutations in the APP gene have been identified and linked to the onset of autosomal dominant AD [64–66]. 

This hypothesis is supported by the correlation between autosomal dominant mutations in both APP and genes coding for parts of the secretase, such as presenilin (PSEN) 1, and PSEN2, with the incidence of AD [36,64,67]. However, reduced clearance of Aβ peptides could also account for their accumulation in the brain.

A protein involved both in the clearance of Aβ and in its ability to aggregate and form fibrils is apolipoprotein E (apoE) [68,69]. Homozygous carriers for the isoform ε4 have about a 12-fold higher risk of developing sporadic AD, while carriers of the less frequent ε2 isoform show a low risk for AD [70,71]. 

Despite all the findings that strongly support the amyloid cascade hypothesis, other data suggest instead that the accumulation of senile plaques in the brain does not correlate with cognitive impairment. 

Indeed, massive cerebral accumulation of Aβ plaques has also been observed in individuals without any cognitive impairment. Additionally, the reduction of Aβ load by immunotherapy does not improve cognition in AD patients [72]. Furthermore, all clinical trials carried out so far targeting either the production or the accumulation of Aβ have failed. 

The debate is fervent in the literature and undoubtedly more studies are needed to clarify the precise mechanism(s) by which Aβ deposits lead to tangle formation, and thus neurodegeneration [3].

2.2. Neurofibrillary Tangles

Neurofibrillary tangles are considered essential for the neuropathological diagnosis of AD [26]. They are intraneuronal bundles of filaments made of hyperphosphorylated microtubule-associated tau proteins [73]. 

Their accumulation causes a loss of cytoskeletal microtubules and tubulin-associated proteins, resulting in morphological modifications in neuronal dendrites and axons [74]. 

Since NFT's appearance in the brain seems to follow a pattern, in a seminal paper, Braak and Braak proposed to classify AD in six stages based on neuropathological findings [44,75]. At physiological conditions, the protein tau is mainly localized in the axon, and it is essential for the stabilization of microtubules [76]. 

Its phosphorylation is highly probable because tau has 85 potential sites of phosphorylation that are easily accessible because of the unfolded structure of the protein [77]. Tau has been found mislocalized (missorted) into the somatodendritic compartment at the early stages of AD. 

Since NFT load correlates with cognitive decline and synapse loss [74], a role for tau missorting has been proposed in AD [78], which serves as diagnostic criteria for the staging of disease progression [79]. 

Interestingly, abnormal phosphorylation of tau is detectable even before NFT formation. In agreement, the reduction of tau has beneficial effects in preclinical AD models, whereas tau mislocalization from axons to dendrites has detrimental effects [80,81]. 

In general, the major modifications of tau found in AD are hyperphosphorylation, missorting, aggregation to oligomers and filaments forming paired helical filaments, dissociation from microtubules, and other post-translational modifications [78]. 

Mutations in genes encoding for tau have not been linked to AD. However, tau knockout mice show very mild neurite outgrowth changes and no microtubule-related defects [82,83]. Human findings showed that microtubule density is decreased in AD patients, but this reduction is surprisingly unrelated to tau abnormalities [84]. 

Consistent with the above, a simple loss of function of tau is not enough to explain the loss of microtubules observed in AD and other mechanisms are probably involved. Several tau-targeting therapies for AD have been proposed. 

These approaches are based mainly on (i) inhibition of kinases (responsible for aberrant tau phosphorylation), (ii) inhibition of tau aggregation, and (iii) stabilization of microtubules. Immunotherapies targeting tau in clinical trials have shown high toxicity and/or lack of efficacy and have been discontinued [85].

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