Astrocyte Dysregulation and Calcium Ion Imbalance May Link the Development of Osteoporosis and Alzheimer’s Disease

INTRODUCTION

Dementia could be divided into five subtypes, including Alzheimer’s disease (AD), Lewy body dementia, frontotemporal dementia, vascular dementia, and mixed dementias [1]. Among these, AD is by far the most common [2]. AD refers to a specific onset and process of age-related cognitive and functional decline, which ultimately leads to death [3]. It is a degenerative disease with cognitive decline as the main manifestation, including memory change and decreased ability to orient [4–6]. During the course of illness, up to 70–80% of AD patients exhibit non-cognitive symptoms. This cause dysphoria in the patient, manifesting as delusions, depression, hallucinations, misidentifications, sleep disturbance, apathy, aggression, eating disorders, inappropriate sexual behaviors, or wandering [7]. Pathologically, the main features of AD include amyloid-β (Aβ) plaques [8], tau hyperphosphorylation [9], cholinergic dysfunction [8, 10], synaptic dysfunction and extensive neuronal loss [11–13], inflammation, and oxidative stress secondary to neurofibrillary tangles and senile plaques [14–16]. In terms of hormones, there may be some imbalance of bone and calcium metabolism hormones [17–26] and a decreased production of melatonin [27, 28].

However, Jack et al. found that the typical sym-ptoms of AD, Aβ plaques and tau hyperphosphorylation, were formed after pathogenesis [29]. Indeed, treatments to eliminate Aβ plaques and tau hyperphosphorylation were shown to have no significant efficacy in reducing symptoms of the disease [30].

Compared with other type of dementias, AD has an obvious feature: decreased pineal gland volume and calcification [31, 32]. The pineal gland secretion capacity is directly proportional to the volume and function of the pineal gland [33, 34]. Pineal calcification, also called “brain sand,” is caused by the deposition of hydroxyapatite in the pineal gland [35, 36]. Pineal calcification will reduce melatonin production that is directly associated with the development of neurodegenerative diseases such as AD [37–39].

The pineal gland, a type of endocrine gland, is an oval shaped structure within the mammalian brain. It is a highly vascularized structure that does not rely on the blood-brain barrier (BBB) for protection [40]. It is composed mainly of astrocytes, microglia, endothelial cells, and pinealocytes that release melatonin [41].

Astrocytes serve a variety of active roles in maintaining normal brain physiology such as secreting several active compounds, forming the BBB, metabolizing several neurotransmitters, and maintaining the ionic balance of the extracellular environment [42]. The end of perivascular astrocytes forms a “rosette”-like structure on the surface of brain capillaries, which is believed to provide optimal two-way induction and communication between astrocytes and endothelium. While not forming a physical barrier, so they preserve the free diffusion between the endothelium and the brain parenchyma [43]. The single astrocyte or astrocytes between the brain regions respond to diverse stimuli by the altered intracellular concentration of calcium ions (that is, [Ca^2 +]_i) [44–48]. The area of astrocyte [Ca^2 +]_i suggests that the signals may represent a form of excitability used for communication [49–52]. Astrocytic [Ca^2 +]_i changes occur in most brain regions and in response to the release of numerous neurotransmitters and cytokines [48]. Calcium is involved in many aspects of neuronal physiology, including activity, growth, and differentiation; synaptic plasticity; and memory and learning, as well as in the pathophysiology of degeneration, apoptosis, and necrosis [53]. The astrocytes propagate intercellular Ca^2 + waves over long distances in response to stimulation; like neurons, they release transmitters (called gliotransmitters) in a Ca^2 +-dependent manner. Astrocytes signal to neurons through Ca^2 +-dependent glutamate release has been considered as evidence of the existence of a vesicle mechanism for regulating the exocytosis of gliotransmitters [45].

The calcium wave is defined as a local increase in cytosolic Ca^2 +, followed by a series of similar events in a wave-like manner. In the intracellular environment, these waves can be restricted to one cell or transmitted to adjacent cells. The steps that lead to intracellular waves in astrocytes usually involve the activation of G-protein-coupled receptors, the activation of phospholipase C, and the production of inositol trisphosphate (IP₃). After the IP₃ receptors are activated, Ca^2 + is released from the endoplasmic reticulum (ER) [54–56]. These intracellular Ca^2 + signals are complex events in space and time, involving the recruitment of basic Ca^2 + release sites, and then spread throughout the cell through an amplification mechanism [57].

Once triggered, intracellular Ca^2 + can be transmitted to neighboring cells as intercellular Ca^2 + waves (ICWs). Regardless of the propagation mechanism of these waves, the Ca^2 + mechanism that triggers the transients of adjacent astrocytes depends on the production of IP₃ and the subsequent release of Ca^2 + from the ER. In addition, ICWs can also transfer via the extracellular messenger, adenosine triphosphate, allowing them to then activate other astrocytes [58, 59]. As summarized above, the extent to which these ICWs can spread is controlled by the effective diffusion properties of Ca^2 +, which allow it to mobilize signaling molecules within and between cells [60].

Ca^2 + represents one of the most important neurotransmitters employed in living cells [61, 62]. Most of the body’s calcium is stored in the bones, and the vertebrate uses the bones as source of calcium to maintain calcium homeostasis throughout their lives [63]. Bone tissue is composed mainly of osteoblasts, osteocytes, and osteoclasts. Osteoblasts are bone-forming cells, osteocytes are mature bone cells, and osteoclasts break down and reabsorb bone. Of these, the osteocyte is a type of astrocyte found in bone. As the most numerous type of cell found in mature bone, it has the potential to live as long as the organism itself [64]. Osteocytes play an important role in bone biology, especially in the remodel process, because they can regulate the activity of both osteoblasts and osteoclasts [65]. When stimulated by the blood, both osteoblasts and osteoclasts can change shape very quickly, within about 15 minutes [66]. When blood calcium levels decrease below normal, osteoclasts release calcium from the bones to assure an adequate supply for metabolic needs. In contrast, when blood calcium levels increase, osteoblasts store the excess calcium in the bone matrix [65, 68]. In order to maintain the integrity of bones, bones are continuously remodeled through a process involving steady-state adjustment of bone structure and composition [69–70]. This dynamic process of calcium release and storage is almost continuous. Therefore, a long-term imbalance in the mechanism may indicate osteoporosis.

According to the above, one of the most important functions of astrocytes is to maintain a balance in ion concentration. The pineal gland is composed of many astrocytes; in bone, the osteocyte is also a type of astrocyte. Therefore, we deduced that, when astrocytes are gradually disabled, calcium may be lost from the skeleton and lead to osteoporosis. Calcium ions released into the blood may accumulate in the pineal gland and cause ectopic calcification [71], which promotes the occurrence of AD.

In fact, a two-year longitudinal study had showed that AD patients lost more bone density than the non-demented group [72]. The study by Kwon et al. also found that the increased occurrence of AD patients with osteoporosis, independent of income, residential area, obesity, smoking, drinking, hyperlipidemia, hypertension, or blood glucose level [73]. And other studies had the same results, too [74, 75].

In terms of drugs, some reports indicate that using calcium-channel blockers [65] and bisphosphonates, a drug used to treat osteoporosis, can effectively alleviate the symptoms of AD [77–79].

In addition, some studies also have pointed out that certain hormones, such as melatonin, bone and calcium metabolism hormones, can affect both AD and osteoporosis. Estrogen [80, 81], parathyroid hormone [82–84], vitamin D3 [85, 86], calcitonin [87–90], and osteocalcin [91] are generally known as the bone and calcium metabolism hormones. But they are also related to AD [17–26], and further pointed out that they are all associated with astrocytes to some extent [92–105].

Brain estrogen is synthesized by astrocytes and also works locally at the site of synthesis in paracrine and/or intracranial fashion to maintain important tissue-specific and neuroprotection functions [17, 92]. Parathyroid hormone-related protein was expressed in immature or transformed human astrocytes, but not in normal cells [98]. The concentrations of parathyroid hormone-related protein were positively correlated with concentrations of tau hyperphosphorylation but reduced upon progression to AD pathology [19]. Vitamin D3 was a vital neurosteroid hormone playing a wide variety of essential protective and regulatory roles in the brain [22]. The study found that astrocyte activation was suppressed after the administration of vitamin D3 in neonatal rats injected with lipopolysaccharide in vivo [100]. Hana et al. suggests that the calcitonin gene-related peptide antagonists might be a therapeutic target to attenuate the pathological cascade and delay cognitive decline of AD in humans [24]. It showed an increased expression in motor neurons following axonomy, play a role as signaling molecules mediating the interactions between the damaged neurons and surrounding glial cells [106]. Osteoblast-derived osteocalcin can improve age-related cognitive decline [26] and prevents anxiety and depression [107], as well as reduces astrocyte and microglia proliferation [105].

Melatonin is the main hormone produced by the pineal gland and secreted into the blood. It is produced in a circadian rhythm and is most produced in the dark phase. The 24-hour rhythm of melatonin production is robust in young animals, including humans, but this cycle deteriorates during aging [108]. The pineal gland of AD patients is gradually calcified with aging, resulting in a decline in melatonin production [109, 110]. The blood melatonin level slowly drops at the beginning of puberty. This decrease in melatonin secretion will continue with age, so that the levels may drop to the point where they may trigger or initiate neurodegenerative changes in the brain [108]. Melatonin production is not only a well-known effect of brain function, but current research has also reported it linked to bone formation. As the study of Nakade et al. demonstrated, in vitro melatonin increased the proliferation of both normal human bone cells and osteoblastic cells and increased the cellular production of procollagen type I c-peptide in human bone cells [111]. Melatonin also increases the gene expression of salivary proteins and other bone marker proteins, such as alkaline phosphatase and osteocalcin [112]. In addition to humans, the phenomenon of increased bone mass with melatonin production also appears in different species, including zebrafish [113] and neu female mice [114].

CONCLUSIONS

Whether it is melatonin produced by the pineal gland or bone and calcium metabolism hormones through these hormones, we know that there may be some correlation between AD and osteoporosis. Furthermore, the fact that osteoporosis and AD are two common age-related disorders raises the possibility that these two organs (brain and skeleton) are interconnected in terms of disease pathogenesis [115]. The greatest commonality of the two disorders is that the involved organs have high percentages of astrocytes. Accordingly, we speculate that osteoporosis and AD are both caused by the long-term imbalance of Ca^2 + in vivo, which is a result of aging or the mutations in astrocytes.

DISCLOSURE STATEMENT

Authors’ disclosures available online (https://www.j-alz.com/manuscript-disclosures/22-0218r1).