Alternative Targets To Fight Alzheimer’s Disease: Focus On Astrocytes Part 3

3.1. Targeting Astrocyte Senescence

Aging is considered one of the main risk factors for the development of neurodegenerative diseases, including AD [220]. 

As people age, all aspects of the body will gradually age, and memory is no exception. However, we can use certain methods to delay the effects of aging on memory and maintain a healthy brain.

First of all, good living habits are very important for maintaining a healthy brain. Maintain adequate sleep, moderate exercise, and a reasonable diet. Studies have shown that staying up late or lacking sleep for a long time can damage brain cells and affect memory. Moderate exercise can promote blood circulation, increase oxygen supply, and improve brain function. At the same time, we must adhere to a healthy diet and consume more foods rich in protein, vitamins, and minerals, such as fish, eggs, beans, etc.

Secondly, learning new knowledge and constantly challenging yourself is also very important for protecting the brain and improving memory. For example, learning a new language or acquiring a new skill can stimulate the activity of neurons in the brain and maintain the flexibility of the brain. In addition, by participating in intellectual games and puzzles of a certain difficulty, the activity of the brain can also be improved and memory can be maintained.

Finally, a positive attitude and social activities are also very important for maintaining a healthy brain and improving memory. Negative emotions such as stress and mood swings will produce stress hormones, which will damage the brain. Therefore, it is very important to understand your emotions and keep your mentality stable. At the same time, you can join social groups, participate in various activities, enrich your life, and maintain a positive mood.

In summary, although aging will have an impact on memory, we can delay this impact and maintain a healthy brain through good living habits, learning new knowledge, a positive attitude, and social activities. Let us look to the future and welcome a better life. It can be seen that we need to improve our memory, and Cistanche can significantly improve memory because it can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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Studies on cellular aging are attracting much attention as a fervent area of research [221,222], and recent evidence demonstrates that astrocyte senescence has a critical role in the pathogenesis of AD. 

As time goes by, astrocytes show peculiar cellular and molecular changes assuming the so-called senescence-associated secretory phenotype (SASP) [223]. This is accompanied by upregulation and release of proinflammatory cytokines, including interleukin(IL)-1β and IL-6, chemokines, and proteinases [175,184,224]. 

Overexpression of intermediate filament proteins glial fibrillary acidic protein (GFAP) and vimentin occurs, whereas neurotrophic growth factors result downregulated. The chromatin undergoes several modifications, and there is upregulation of p53, p21WAF1, and p16INK4A, leading to a permanent cell cycle arrest [225,226]. 

These features may not be specific senescence markers for astrocytes since they are postmitotic cells that do not usually divide in healthy tissues [126]. Regardless, one of the most common features of aging is the accumulation of senescent cells. 

Bussian et al. demonstrated that the presence of senescent astrocytes and microglia in a mouse model of aggressive tauopathy (the PS19 mice) promotes the formation of hyperphosphorylated tau aggregates. 

Removing p16INK4A-expressing senescent cells through a genetic approach prevented astrogliosis, hyperphosphorylation of tau, degeneration of cortical and hippocampal neurons, and it preserved transgenic mouse cognitive functions [182]. Comparable effects have been obtained by testing a senolytic agent, the orally active anticancer drug ABT263 (navitoclax), that acts as inhibiting Bcl-2. 

By this mechanism, this compound can induce apoptosis specifically in senescent cells [227]. The clearance of accumulated senescent astrocytes also rescued in vivo the radiation-induced impaired astrocytic neurovascular coupling and mice cognitive performance [181]. 

Another report showed that the overexpression of an inhibitory isoform of p53, the ∆133p53, which is downregulated in AD, repressed the SASP after its induction in astrocytes by exposure to radiation. ∆133p53 overexpression promoted also DNA repair and inhibited irradiated astrocyte-mediated neuroinflammation and neurotoxicity [183]. 

The antiprotozoal drug pentamidine upregulates p53 and increases the ratio BAX/Bcl2, ultimately promoting apoptosis in cultured astroglioma cells [228], and it exerts anti-inflammatory effects in mice receiving human Aβ42 into the hippocampus [229]. 

Finally, from the field of phytotherapy, an in vitro study showed that Ginsenoside F1 suppresses the SASP in astrocytes by downregulating the p38MAPK-dependent NF-κB activity [184], a pathway upregulated in AD.

3.2. Targeting Astrocyte Glutamate Transporters

Glutamate represents the major excitatory neurotransmitter of the CNS, whose neurotransmission is finely regulated by both neurons and glial cells [230]. Astrocytes, in particular, are responsible for glutamate reuptake from the synaptic cleft through excitatory amino acid transporters (EAATs). 

There are five subtypes of EAATs (EAAT1–EAAT5), but EAAT2 (glutamate transporter-1/GLT1) is responsible for more than 90% of glutamate reuptake [231]. Once inside the astrocyte, glutamate is converted mainly into glutamine by the glutamine synthetase (GS) and then shuttled back to the presynaptic neuron, which uses it to synthesize glutamate again. 

A portion of glutamate is converted to gamma-aminobutyric acid (GABA), which is usually catabolized. The glutamate-glutamine shuttle is crucial for glutamate homeostasis, and thereby for learning and memory. 

If the shuttle is dysfunctional, an abnormal glutamate stimulation could occur, which is neurotoxic [232]. Glutamate excitotoxicity has been observed in AD and correlated with cognitive decline [232,233]. 

In parallel, both accumulation of GABA, whose concentration is low in astrocytes under physiological circumstances [234], and its release from reactive astrocytes have been observed in transgenic animal models of AD (5xFAD and APP/PS1 mice), resulting in memory deficits [235,236]. However, astrocytic GABA content seems to follow a bell-shaped curve along aging and does not relate to Aβ [237]. 

Human postmortem AD brains showed altered expression of several GABA transporters in cortical and hippocampal regions [238]. Therefore, counteracting dysfunctions in the content of neurotransmitters and the expression of their transporters could likely be beneficial in AD. 

Research targeting the modulation of astrocytic GABA is still not fully explored, and further studies are warranted. Instead, the enhancement of glutamate transporter function and expression has been tested using various activators in several neurological diseases [239]; however, few studies were carried out in AD models. 

β-lactam antibiotics are drugs that upregulate GLT1 gene transcription, in addition to having antibacterial effects [240,241]. Among them, ceftriaxone was found to ameliorate AD pathology by improving spatial learning and memory in APP/PS1 mice, upregulating the expression of both GS and the system N glutamine transporter 1 (SN1) [185]. 

Another drug already approved for human use is riluzole, which has been shown to improve memory performance in aged rats and 5xFAD mice [186,242]. Riluzole is a neuroprotective agent able to increase Na+ -dependent glutamate uptake in synaptosomes in a dose-dependent manner [243]. 

Riluzole chronic oral administration prevents age-related gene expression changes in rats' hippocampi [244] and reduces the levels of Aβ42 and Aβ40 oligomers and neuritic plaques in 5xFAD mice [186]. Despite being so promising, these results have not been translated into the clinic yet.

3.3. Targeting the Astrocytic Metabolic System

As we mentioned before, the failure of astrocytes to support neuronal energy needs could facilitate the progression from physiological to pathological brain aging. 

For instance, the metabolic products of fatty acid oxidation decrease during AD [245], making lipid metabolism a potential target for AD treatment. Recently, an in vitro study found that activation of the peroxisome proliferator-activated receptor proliferator-activated receptor (PPAR) beta/delta (PPARβ/δ) increases fatty acid oxidation [187]. 

Indeed, a rate-limiting enzyme of fatty acid oxidation is the carnitine palmitoyltransferase 1A (CPT1A), which catalyzes the transfer of fatty acids into the mitochondria, where the β-oxidation occurs. 

Konttinen et al. tested the effects of GW0742, a synthetic PPARβ/δ agonist, in human astrocytes obtained from pluripotent stem cells (iPSCs) of AD patients carrying an amyloidogenic mutation of PSEN1 (PSEN1∆E9). 

GW0742 enhanced the expression of CPT1a, increasing astrocyte fatty acid oxidation [187]. In primary astrocytes obtained by 5xFAD mice, which show an altered metabolic profile, administration of the vitamin B5 precursor pantethine reversed several metabolic alterations induced by Aβ challenge, including (i) altered activity of the glucose-6-phosphate dehydrogenase, the α-ketoglutarate dehydrogenase complex, and the succinate dehydrogenase; (ii) decreased ATP production; and (iii) altered expression of the hypoxia-inducible factor-1 alpha, known to protect against Aβ toxicity. 

Pantethine treatment showed some anti-inflammatory actions by downregulating IL-1β expression [188]. Similarly, treatment of the astroglioma cell line C6 with hydroxytyrosol, the major polyphenol contained in olives, ameliorated the metabolism of glucose, previously altered by Aβ(25–35) challenge, through activation of Akt [189].

Evidence demonstrates the ability of glucagon-like peptide-1 (GLP-1) to improve cognitive deficits in AD [246]. Zheng et al. just published that this effect is related to GLP-1's ability to restore in vitro the Aβ-induced glycolysis impairment in astrocytes, by activating the PI3K/Akt pathway [190]. 

A recent study by Wang et al. demonstrated that metformin, a hypoglycemic drug of clinical use, exerts anti-inflammatory and antioxidant effects in rat primary astrocytes treated with high glucose concentration [191], strengthening the link between altered metabolism and induction of the inflammatory process.

3.4. Upregulation of Astrocytic Neurotrophins and Growth Factors

Neurotrophic factors imbalance and dysregulation are associated with neurodegenerative diseases, including AD [247]. The brain-derived neurotrophic factor (BDNF) is involved in cognition and memory formation, given its role in modulating synaptic plasticity. Astrocytes can release neurotrophic growth factors, including BDNF, exerting protective effects on neurons [248]. 

Thus, the increase in astrocyte neurotrophic factor expression and release could be a therapeutic approach for AD [249]. Sawamoto et al. found that the citrus flavonoid 3,5,6,7,8,30,40-heptamethoxyflavone (HMF) exerts neuroprotective effects by increasing the expression of BDNF in astrocytes within the hippocampus of mice and in the C6 glioma cell line. 

The BDNF increase was induced by the activation of cAMP/ERK/CREB signaling and inhibition of phosphodiesterase 4B and 4D [192]. Another molecule found to be able to upregulate BDNF expression in cultured astrocytes is quetiapine, a widely used atypical antipsychotic drug [193]. Recently, a paper in which transgene delivery in astrocytes was used to obtain the upregulation of BDNF in 5xFAD mice was published [194]. 

Specifically, 5xFAD mice were crossed with transgenic pGFAPBDNF mice, expressing BDNF under the GFAP promoter. The resulting transgenic mice showed restored levels of BDNF, compared to 5xFAD mice, which have reduced levels of this neurotrophin compared to their wild-type counterparts. BDNF restoration also resulted in improvements in cognitive tasks and ameliorated synaptic plasticity [194]. 

Some studies have also explored the potential beneficial effects of neural stem cell transplantation in models of AD. An Indian group studied the lineage-negative stem cells (Lin-ve) derived from human umbilical cord blood (hUCB) in an animal model of Aβ42-induced injury. They found that intrahippocampal transplant of these cells at specific dosage and timing shows potential to reverse hippocampal Aβ42-induced mouse cognitive impairment, measured by Morris water maze and passive avoidance, through a neuroprotective mechanism likely mediated by BDNF upregulation [195,250]. 

Blockade of the BDNF-TrkB pathway by systemic administration of a TrkB inhibitor nullified the benefit of Lin-ve cell transplant. Aβ42-challenged mice showed decreased BDNF and GFAP protein and gene expression, which were both reversed by Lin-ve cell transplant. Some less clear effects were detected also in the expression levels of both the glial-derived neurotrophic factor (GDNF) and the ciliary neurotrophic factor (CNTF), which deserve further studies [195]. 

AD pathogenesis is also affected by altered production of growth factors [251,252], including the fibroblast growth factor (FGF) 2 [247]. In particular, FGF2 is increased in reactive astrocytes around senile plaques [253]. Last year, Chen et al. demonstrated that FGF2 has protective effects against Aβ42-induced cytotoxicity in primary cultured cortical astrocytes. 

In their experiments, primary astrocytes challenged with Aβ42 were treated with either high or low-molecular-weight forms of FGF2. The low molecular isoform of FGF2 promoted astrocyte proliferation, enhancing the expression of c-Myc, Cyclin D1, and Cyclin E [196].

3.5. Targeting Astrocytes-Driven Amyloid Aggregation and Clearance

Accumulation of Aβ could be the result of its increased synthesis reduced clearance or a combination of both. Looking for AD treatment, an important area of investigation targets Aβ clearance, which depends, at least in part, on astrocytes. 

Indeed, astrocytes can take up Aβ and digest it in their lysosomes. However, the astrocytic degrading machine could get engulfed, leading to detrimental consequences [254]. Lysosome functions and gene expression for proteins involved in both autophagy and proteolysis were found altered in aging and AD [255,256]. Two of the apolipoproteins associated with a high risk for developing sporadic AD are secreted by astrocytes and are involved in Aβ aggregation and clearance, the apoE4 and the apoJ (also known as clusterin) [69,257]. 

The apoE4, once secreted by astrocytes, binds to high-density lipoprotein (HDL)-like particles, and the level of its lipidation influences Aβ aggregation and clearance [258]. Chernick et al.demonstrated the ability of an HDL mimetic peptide, the 4F, to increase apoE4 lipidation in primary human and murine astrocytes. 

That counteracts the Aβ-induced accumulation of intracellular apoE4, mitigating Aβ detrimental effects on proper cellular trafficking and functionality of apoE [197]. Clusterin (Clu) is a ubiquitous protein whose functions are still not clear, but studies have shown its involvement in Aβ aggregation, toxicity, and clearance. Conflicting results have been published reporting both neuroprotective and detrimental properties of Clu [259,260]. 

Novel in vitro findings demonstrated a role for astrocytic Cluin promoting synapse formation and glutamatergic synaptic activity [199]. Wojtas et al.overexpressed Clu (>about 30%) selectively in GFAP-positive astrocytes of APP/PS1mice and noticed a reduction in Aβ accumulation and formation of fibrillary deposits in both cortex and hippocampus compared to control animals. 

In the same brain areas, the authors found that Clu overexpression was associated with a reduction in the number of cortical and hippocampal dystrophic neurites [198]. In accordance, the reduction (<about 50%) in Clu expression in GFAP-positive astrocytes of APP/PS1 mice leads to a worsening of the AD-like outcomes [198]. 

Novel in vivo findings demonstrated that Clu overexpression in astrocytes enhances excitatory neurotransmission and rescues the synaptic deficit in Clu knockout mice. Clu overexpression in GFAP-positive astrocytes of 5xFAD mice reduced plaque numbers and plaque size and rescued presynaptic dysfunction [199].

Another molecule that seems to promote Aβ clearance is the epigallocatechin gallate (EGCG), a member of the catechin family. In cultured astrocytes, ECGC elevates neprilysin (NEP) expression, one of the most important Aβ-degrading enzymes in the brain, involving also the activation of ERK and phosphoinositide 3-kinase [200].

Moreover, oral administration of fish oil, containing n-3 polyunsaturated fatty acids (PUFAs), was found effective in clearing Aβ from the brain of fat-1 transgenic mice [201], but not of aquaporin (AQP) 4 knockout mice, suggesting the involvement of AQP4 protein, expressed selectively in astrocytes, in Aβ clearance. 

Additionally, PUFA administration protects from AQP4 polarization occurring after Aβ injection [201], a sign of astrocytic dysfunction [261].

3.6. Targeting Astrocytic Reactivity, Complement Cascade, Neuroinflammation, and Oxidative Stress

Neuroinflammation plays a pivotal role in the development and progression of AD. Indeed, Aβ plaques are surrounded by activated glial cells, and Aβ itself leads to the activation of astrocytes and microglia, together with the release of proinflammatory factors [97,262–264]. 

Brains of different transgenic mouse models of AD show activated astrocytes, even before the appearance of plaques and NFTs [265,266]. When astrogliosis occurs, reactive astrocytes produce inflammatory markers, such as tumor necrosis factor (TNF)-α, IL-1β, and IL-6, and calcineurin, a protein phosphatase that mediates inflammatory responses. 

This is associated with a wide number of cellular events, including the aforementioned activation of the complement cascade, the release of nitric oxide, and ROS. This phenomenon is normally engaged with the intent of defending the brain by removing injurious stimuli (e.g., Aβ fibrils phagocytosis). However, if prolonged beyond physiological limits, it would have detrimental effects. 

Therefore, targeting astrocyte reactivity and, consequently, the related activation of the complement cascade, the oxidative stress, and the inflammatory response could represent an effective therapeutic strategy in AD. A compound that has shown such properties is cannabidiol, the main nonpsychoactive component of Cannabis Sativa [267]. 

Studies demonstrated cannabidiol effects in reducing both GFAP and S100B mRNA and protein expression, as well as neuroinflammatory parameters in different models of AD [268–270]. The complement component C3 is increased in human AD brains, and it is expressed by reactive astrocytes. 

Its increased expression is required for neurodegeneration to occur [271]; thus, its targeting could be beneficial. Indeed, Shi et al. compared aged plaque rich transgenic APP/PS1 mice knockout (KO) for the C3 to transgenic APP/PS1 mice to evaluate Aβ plaque pathology, glial responses to plaques, and neuronal dysfunction in the brains. 

They found that C3 KO mice had less activation of glial cells at the center of Aβ plaques compared to control mice, suggesting that the downregulation of C3 controls astrocyte activation and neuroinflammation in AD [202]. 

Mc Manus et al. tested the effect of infection by Bordetella Pertussis in APP/PS1 mice and the potential benefit of fingolimod (FTY720) administration, an FDA-approved immunomodulatory drug for treating multiple sclerosis. 

Fingolimod reduced signs of infection-induced BBB increased permeability, GFAP immunoreactivity, and Aβ deposits, compared to control mice. Results of additional in vitro experiments in primary astrocytes suggested that the decreased Aβ accumulation was driven by the fingolimod-induced increase in the phagocytic capacity of astrocytes [203]. 

Since Aβ activates the astrocytic inflammasome promoting the release of IL-1β, Couturier et al. demonstrated that the downregulation of this Aβ-induced inflammatory process increases Aβ phagocytosis in astrocytes in vitro. That is due to the release of the chemokine CCL3, ultimately improving in vivo the memory deficits of 5xFAD mice [204]. 

Therefore, that phlogistic event represents a druggable therapeutic target, which still needs to be thoroughly investigated. Several molecules have been tested during the last years for their ability to dampen astrocyte reactivity in AD [269,270,272,273], but none have been translated to the clinic yet. Patients with MCI and vascular dementia show increased levels of Lipocalin 2 (Lcn2) in the CSF. 

In AD cases (stages V and VI), Lcn2 immunoreactivity increased in reactive astrocytes localized around plaques and in reactive microglia [274]. Astrocytes are the major producers of Lcn2 in the brain [275]. This protein is involved in several processes including inflammation, iron metabolism, cell death, and cell survival, modulating the cellular response to Aβ [275]. 

Staurenghi et al. demonstrated that increased levels of oxysterols observed in mild or severe AD brains, accompanied by increased levels of Lcn2, determine a clear morphological change in mouse primary astrocytes [276]. 

A recent study found that the iron chelators deferoxamine and deferiprone reduce Aβinduced iron accumulation in astrocytes and inhibit Aβ-induced Lcn2, suggesting these molecules as promising therapeutic strategies against AD [205]. 

A novel synthesized compound, Glu-DAPPD, containing a glucose group linked to an anti-neuroinflammatory agent, the N, N0 -diacetyl-p-phenylenediamine, showed in vivo to reduce Aβ aggregates and immunostaining for astrocytes and microglia, and to improve cognitive function in transgenic APP/PS1 mice being administered chronically for two months [206].

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