Alternative Targets To Fight Alzheimer’s Disease: Focus On Astrocytes Part 2

2.3. Unfolded Protein Response and Defective Proteostasis

AD is a neurological disease characterized by the ubiquitous association of misfolded and aggregated proteins, whose role in the pathogenesis and progression of the disease is still unclear. 

The nervous system is the control center of the human brain. It is a complex system responsible for the functioning of all parts of our body. This system includes our thinking, actions, emotions, memory, etc. A healthy nervous system is essential for maintaining the normal function of the body and improving memory.

Many people face neurological diseases, such as Alzheimer's or Parkinson's disease. These diseases can affect people's quality of life, but it does not mean they cannot have a healthy memory. There are many ways to improve and enhance memory, even in the face of these diseases.

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Secondly, a good diet and sleep are also very important. Some foods, such as fish and chia seeds, are rich in Omega-3 fatty acids, which help promote brain health. On the other hand, sleep is very important for brain recovery because sleep helps promote memory transfer and retention of specific information.

Finally, it is crucial to keep your emotions positive. Long-term stress, worry, fear, and other emotions can affect people's memory. On the contrary, by practicing meditation, yoga or other relaxation methods, tension and anxiety can be reduced, which can help improve memory.

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However, it is reasonable to hypothesize that a significant dysfunction in protein homeostasis (proteostasis) occurs. Proteostasis is complex since it requires proteins to be in a specific localization, aggregation, concentration, and conformation. 

Multiple events occurring in AD have been suggested to act as proteostasis perturbators, including NFTs [86], neuroinflammation [87], altered calcium signaling [88], mitochondrial energy imbalance [89], and oxidative stress [90]. 

Most of these have been linked to endoplasmic reticulum (ER) stress [91]. The ER is an essential organelle in eukaryotes responsible for the synthesis and folding of all secretory and membrane proteins [92]. 

Under physiological conditions, when aberrant proteins are synthesized, the ER exports them to the cytosol, where they are directed to the ubiquitin-proteasome system for degradation [93]. 

In AD, the massive accumulation of aberrant misfolded proteins at the ER engages the unfolded protein response (UPR), a complex signaling system stress response that orchestrates protein folding and initiates apoptosis, or autophagy, in irreversibly damaged cells [94]. Growing evidence indicates that ER stress responses may also affect metabolic pathways that generate Aβ, suggesting its direct role in AD etiology. 

For instance, it has been demonstrated that UPR signaling events increase BACE1 levels, causing Aβ overproduction and promoting the transcription of the PSEN gene [95].

2.4. Complement Cascade and Neuroinflammation

Inflammation has been recognized as a key component of AD pathology [96], likely contributing even to the progression of the disease [97,98]. Several transcription factors involved in the inflammatory responses have been found involved in AD. 

For example, the CCAAT/enhancer-binding protein (c/EBP) family of transcription factors is elevated in the brains of AD patients, compared to healthy controls [99], and it was found to promote microglial neuroinflammatory response [100]. Another example is the NF-kB pathway that controls cytokine production and cell survival, which is strongly associated with AD neuroinflammation [101]. 

Both the classical and alternative complement pathways are induced in vitro by fibrillar Aβ [102] and NFTs [103]. Senile plaques colocalize with microglia and many proteins of the complement cascade in animal models of the disease and human AD [62,104–106]. Moreover, human AD brains show signs of activation of the complement in the same areas presenting senile plaques and NFTs [107]. 

Complement factors are elevated during AD progression, likely as a general reaction to abnormal protein deposition and other cerebral injuries that occur in the AD brain [108–110]. 

This is not surprising, since the complement cascade is a fundamental effector of the innate immune system that favors the rapid clearance of pathogens, apoptotic cells, and their debris, as well as the extent and termination of the inflammatory immune response [111]. Some components of the complement cascade play a key role in synapse pruning. 

This process is active and fundamental during the development of the nervous system. However, it is scarcely seen in the adult brain when its occurrence is thought to be detrimental, as in AD brains. Indeed, evidence of excessive complement-mediated synapse pruning has been reported in AD and animal models of aging [112–114]. 

Regardless, some human evidence shows inconsistency between blood and cerebrospinal fluid (CSF) concentration of complement proteins [110], highlighting the heterogenicity of the pathology, which complicates the path to using complement proteins as diagnostic biomarkers. However, components of the complement could be also potential novel therapeutic targets [111,115]. 

In preclinical models of neurodegenerative disorders, the inhibition of specific complement proteins had beneficial effects [116,117]. Unfortunately, the blood-brain barrier (BBB) is not accessible to current complement-targeted therapeutics, making drug design challenging [117]. Additionally, the molecular mechanisms underlying the inflammatory process observed in AD have not been fully clarified yet. 

This could explain the failure of the clinical trials conducted so far using conventional anti-inflammatory drugs [118–122]. Neuroinflammation is a complex defensive process crucial for the preservation of brain homeostasis that becomes detrimental under certain circumstances, which is not fully understood. 

It is now accepted that any cerebral insult triggers the activation of glial cells in a defensive, preservative process aimed at restoring the lost homeostasis. Both morphological and functional modifications of mainly, but not exclusively, microglia and astrocytes occur accompanied by a pro-inflammatory environment [19]. 

Microglia cells, being the immune sentinels of the central nervous system (CNS), are the first cells responding with a potent inflammatory response, consequently leading to the activation of other glial cell types, including astrocytes [123,124]. 

If the stimuli that activate glial cells are very intense, and/or long-lasting, and/or not counterbalanced by an interruption signal, reactive gliosis could be established and normal brain functioning could be altered, leading even to neuronal death [125]. However, the exact timing and mechanisms that turn neuroinflammation from a physiological to a pathological process are still under study [126,127]. 

Therefore, the clarification of the underlying molecular and cellular mechanisms could allow scientists to develop and test new, and hopefully efficacious, pharmacological treatments. For example, a recent study identified a negative regulator of the transcription factor c/EBPb, responsible for microglia-mediated neuroinflammation, which could represent a novel AD therapeutic target [100]. 

Of note, c/EBPb is expressed also by astrocytes. Thus, additional studies should address the possibilities of targeting it in different cell types involved in the neuroinflammatory process.

2.5. The Neuroenergetic Hypothesis

Glucose is the main brain energy fuel, which crosses the BBB through GLUT1, a membrane-bound glucose transporter. Both aging and AD are associated with a reduction of GLUT1 [128,129]. 

Additionally, transgenic mouse models show a correlation between the decreased density of GLUT1 and Aβ peptide accumulation [129,130]. In aged humans, an association between glucose hypometabolism and apoE genotype has been made [131]. The main signaling that mediates the uptake of glucose inside cells is the interaction of the pancreatic hormone insulin with its receptor. 

AD demented patients show a high level of plasma insulin, while low levels of both CSF insulin and brain insulin receptors. In accordance, insulin resistance has been correlated with dementia, and patients with type-2 diabetes have a much higher risk of developing AD [132]. Indeed, glucose acts as a memory enhancer since the neuronal activity is tightly coupled to glucose utilization [133]. 

Using 5xFAD mice as an AD model, Andersen et al. showed that neuronal GABA synthesis in the brain is directly affected by glucose hypometabolism in astrocytes [134]. Under normal conditions, astrocytes produce ATP and lactate that are released to feed neighboring neurons, in a process known as the astrocyte-neuron lactate shuttle, which energetically supports neurons given their high-energy requirements, such as action potential firing [135–137]. 

This shuttle is necessary for long-term potentiation [135]. Berchtold et al. reported that many genes involved in mitochondrial bioenergetics were upregulated in aged individuals with mild cognitive impairment (MCI), relative to age-matched controls, but downregulated in full-blown AD patients [138]. All this evidence contributed to the so-called neuroenergetic hypothesis, which posits that the chronic progressing starving of brain cells could produce energy-deficiency stress. 

This reduces neuronal firing and induces a shift from pathways associated with physiological APP metabolism to pathological ones, related to Aβ/tau production [139], ultimately leading to AD.

3. Astrocytes as Targets for AD Therapeutics

In the beginning, the interest in glial cells in AD arose mainly from the role played by the microglia cells in the immune response [140]. Afterward, it became clear that all types of glial cells were probably involved in both the etiology and progression of the disease, as actors in the context of the immune response and key regulating elements involved in the molecular and cellular processes altered in AD [141]. 

Indeed, cell-type-specific transcriptomic changes in human AD brains have been associated with distinct molecular pathways [142]. Glial cells are a heterogeneous cell population exerting a plethora of different actions necessary for the correct functioning of the brain [143]. Glial cells are usually classified into microglia and microglia. 

The latter have a neural origin and include astrocytes, oligodendrocytes, and NG-2 glia, also known as synantocytes [144]. Microglia are the main immunocompetent cells of the nervous system with a nonneural origin. Being macrophages, they fulfill primarily defensive functions [145]. These cells regularly scan the surrounding environment with their processes and adapt their morphology and functions depending on what they sense. 

Upon activation, microglia exert chemotactic and phagocytic properties, moving where needed and clearing waste products, cellular debris, and pathogens [146]. In addition to these crucial defensive functions, microglia exert many other key actions related to synapse formation, pruning, and functioning [147–149]. 

Microglia cells show various activation states and expression profiles in both human AD brains and murine AD models [150]. The pathway analysis of single-nucleus transcriptomic experiments revealed that microglial genes mostly related to the immune response were differentially expressed between human AD brains and control subjects [142]. 

Additionally, the mutation in TREM2, a cell surface protein selectively and highly expressed by microglia in the brain, has been associated with a three-fold higher risk of developing AD [151]. Oligodendrocytes originate from precursor cells (OPCs) mainly localized in the ventricular zones of the brain, from which they migrate during development, through which they become mature oligodendrocytes. 

This process starts during the third trimester of gestation and continues throughout life [152]. Oligodendrocyte's main function is the creation of the myelin sheath, crucial for effective neuronal transmission of action potentials [153]. 

Under the myelin sheath, in the internodal personal space, oligodendrocytes establish direct connections with axons via cytoplasmic-rich myelinic channels, in which a bidirectional movement of macromolecules occurs between the two cells [152,154,155]. 

Impairments in myelin formation and functions have implications in several neurodevelopmental and neuropsychiatric disorders [156–160], and the maturation of OPCs into oligodendrocytes is accelerated by the loss of myelin due to injuries, aging, or diseases, including AD [157]. Astrocytes maintain CNS homeostasis at molecular, cellular, organ, and system levels of organization [161]. 

Several morphologically distinct subtypes of astrocytes have been identified that likely correspond to specific functions [162]. Indeed, they are present both in the white and grey matter. 

Astrocytes are key components of the BBB, thus regulating the communication between the CNS and the periphery [163]. They control the CNS microenvironment in several ways, including by buffering extracellular ions and the pH, regulating blood flow through the release of vasoactive molecules, and clearing reactive oxygen species (ROS) [164]. 

Astrocytes are components of the so-called gliocrine system, releasing around 200 molecules, mainly neurotrophic factors, and energy substrates, fundamental for the maintenance of CNS homeostatic functions [165]. 

Astrocytes exert primary roles in synaptic transmission and information processing by neural circuits. It has been demonstrated the ability of a single astrocyte to be in contact with several neurons and to modulate synaptic transmission by tuning neurotransmitter levels in the synaptic cleft [162,163]. Originally classified as OPCs, synantocytes are stellate cells, with large process arborizations that specifically express a new type of chondroitin sulfate proteoglycan [166]. 

They are found both in white and grey matter and interact with other glial cell types and neurons. Synantocytes extend processes along myelin sheaths to contact also the paranodes and nodes of Ranvier. Moreover, they were found to take part in the synaptic cradle, but their specific function at synapses has not been clarified yet [167,168].

Given the essential and pleiotropic functions driven by glial cells, the interest in the involvement of these cells in the pathophysiology of several neurological and neuropsychiatric disorders has grown exponentially in the last few years [169]. 

Additionally, different glial cell types can communicate and influence each other's phenotype and functions. However, the mechanisms and implications of those cross-talks are only beginning to be elucidated [124,170,171]. Below we focus on the evidence supporting a role for impaired astrocyte functioning in AD, and the potential therapeutic benefit that approaches aimed at restoring them could have. 

The role of astrocytes in AD is difficult to decipher, mainly for two reasons: firstly, astrocytes exert a huge plethora of different functions in the CNS that are not easy to tease apart, and secondly, astrocytes respond to any perturbation of CNS homeostasis, caused by either injuries or diseases, with a variety of changes at structural, transcriptional, and functional levels. 

Additionally, the alterations are specific to the astrocyte localization and the CNS insult, and even to the different stages of the disease [125,172–174]. Regarding AD, the evidence available so far suggests the presence of both glial reactivity and atrophy since the initial stages of AD [97]. Additionally, astrocytes close to amyloid plaques show greater transcriptional changes than those far from plaques [175]. 

To complicate the picture, recent human studies showed that postmortem AD brains contain a reduced proportion of neuroprotective astrocytes, which are associated with glutamate recycling and synaptic signaling, compared to controls [142]. 

Moreover, the notion that astrocytes are asthenic in the final stages of AD is gaining ground. Regardless, both reactive and asthenic astrocytes operate erratically, thus contributing differently to the worsening of the disease through neuronal impairment and death [176]. 

Therefore, the difficulty of developing a pharmacological approach targeting astrocytes increases, since a drug directed to hypertrophic astrocytes in a specific AD stage could be detrimental in another stage at which astrocytes are atrophic, and vice versa. 

Moreover, modulating astrocytes could affect the functioning of other glial cell types, besides neurons [177,178], altering the normal communication among brain cells. Another important challenge to overcome when designing a therapy directed to the brain is the necessity for it to cross the BBB. It has been reported that only 5% of about 7000 drugs screened in the Comprehensive Medical Chemistry database enter the CNS passing the BBB [179,180]. 

There is a growing number of reports looking at the role of astrocytes in AD, and several approaches targeting astrocytes have been proposed (Figure 1). The following sections review both in vitro and in vivo evidence that has been published in the last five years targeting astrocytes pharmacologically in models of AD (Table 1).

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