Abstract
Ever increasing incidence of Alzheimer’s diseases (AD) has been reported all over the globe and practically no drug is currently available for its treatment. Since last 15 years, not a single drug came out of clinical trials. The researchers are yet to discover a drug that could specifically target AD, in fact the drugs that are about to launch in the global market either belongs to natural compounds or are already approved drugs targeting other diseases. So, we need to shift our focus on finding novel targets which are more specific and could either detect or inhibit the disease progression at very early stage. Microglia are the only resident innate immune cells of the brain that are originated from erythromyeloid progenitors. They migrate to the brain during early embryonic development, although their number is less (~ 5 to 10%) but they could act as guardians of the brain. It has been shown that the extracellular deposits of Aβ continuously phagocytosed by microglia in healthy individuals, but this ability would decrease with the age and lead to development of AD.
In this review, we have explored the possibility whether microglial cells could be utilized as an early predictor of the AD progression. Here, we have discussed about innate immune response of microglial cells, the factors affecting microglia response, microglial receptors to which Aβ could bind, and microglial phenotype markers. Lastly, we concluded with the list of available AD therapeutics along with their mechanism.
Introduction
Alzheimer’s disease, a common form of dementia, accompanied with loss of memory, impairment in learning and thinking, depression, delusions and other symptoms. According to a recent report, 5.7 million Americans of all age groups are suffering with Alzheimer’s. According to Alzheimer’s association, over 4 million Indians are suffering with some or other form of dementia [1]. Most accepted hallmark of Alzheimer’s is accumulation of Amyloid-beta (Aβ) in the extracellular spaces, interfering within synapse, and other one is excessive phosphorylation of Tau, microtubule associated protein, in the neurons. It has been observed that in some cases Alzheimer’s patients are also suffering from Down’s syndrome, that could be because of APP (amyloid precursor protein) gene and gene responsible for Down’s syndrome are located on chromosome 21 .
Aβ is a peptide of 36-43 amino acids, and is a part of transmembrane protein APP in the neurons.
The peptide is derived from the cleavage of APP by β secretase (BACE- Beta amyloid convertase enzyme) followed by γ secretase (Presenilin 1 and 2) [3, 4]. Initially, Aβ monomers are formed which then aggregated into insoluble fragments and finally forms fibrils and plaques. On the other hand, tau protein accumulates intracellularly as paired helical filaments and obstructs the cellular functions that are performed in the neurons which lead to neurodegeneration with neurofibrillary tangles [5]. So, in this review we have illustrated about the innate immune response of microglial cells; factors affecting microglial response; microglial receptors involved in Aβ uptake, and microglial phenotype markers, by believing that Aβ accumulation is the primary cause of Alzheimer’s development.
Role of glial cells in AD
Glial cells or neuroglial cells of CNS (central nervous system) surrounds the neurons and hold them in place. They also maintain the homeostasis and are of about 10-50 times more than neurons in the CNS. Oligodendrocytes, astrocytes, ependymal cells, and microglia are the different types of glial cells, which maintain normal physiology during the brain development. Recent reports have shown that on knocking out of myelin associated genes Ugt8, Cnp and Plp1 in mouse model, myelin dysfunction and eventually neurodegeneration was observed. Oligodendrocytes has also shown to activate inflammatory pathways in response to Aβ [11]. It has been found that BACE-1 plays an important role in oligodendrocytes mediated myelin production, which was confirmed by BACE inhibitors treatment [12]. Thus, oligodendrocytes indirectly affect the progression of Alzheimer’s. Astrocytes are star shaped cells with fine processes of variable length that differs based on their location. The major function of astrocytes is restoration of water and ion homeostasis as well as they contribute to the BBB maintenance [13]. Aβ presence leads to disturbance in Ca+2 homeostasis of astrocytes, which lead to astrogliosis and cause neuroinflammation [11]. Few reports have revealed that unsaturated fatty acid, palmitate, induced the NLRC4 (NLR family CARD domain-containing protein 4) expression in astrocytes and promotes the AD progression [14]. Ependymal cells form membrane lining of ventricles in the brain as well as spinal cord and produce small amount of cerebrospinal fluid which helps in Aβ clearance from the brain [13]. However, in pathological conditions the lysosomal function of ependymal cells has shown to be altered, and instead of clearance, Aβ gets accumulated [15].
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