The Role of Mesenchymal Stem Cells in Regulating Astrocytes-Related Synapse Dysfunction in Early Alzheimer's Disease

Abstract

Alzheimer's disease (AD), a neurodegenerative disease, is characterized by the presence of extracellular amyloid-β (Aβ) aggregates and intracellular neurofibrillary tangles formed by hyperphosphorylated tau as pathological features and the cognitive decline as main clinical features. An important cellular correlation of cognitive decline in AD is synapse loss. Soluble Aβ oligomer has been proposed to be a crucial early event leading to synapse dysfunction in AD. Astrocytes are crucial for synaptic formation and function, and defects in astrocytic activation and function have been suggested in the pathogenesis of AD. Astrocytes may contribute to synapse dysfunction at an early stage of AD by participating in Aβ metabolism, brain inflammatory response, and synaptic regulation. While mesenchymal stem cells can inhibit astrogliosis, and promote non-reactive astrocytes. They can also induce direct regeneration of neurons and synapses. This review describes the role of mesenchymal stem cells and underlying mechanisms in regulating astrocytes-related Aβ metabolism, neuroinflammation, and synapse dysfunction in early AD, exploring the open questions in this field.

Keywords: Alzheimer’s disease; amyloid β; astrocytes; mesenchymal stem cells; neuroinflammation; synaptic functions.

FIGURE 1

AD pathology and MSCs treatment. (A) The generation of Aβ from APP. (B–D) Changes of AD metabolism. (B) In physiological conditions, APP will gradually be decomposed by BACE1 and γ-secretase. RAGE and LRPs, together with NEP on the blood brain barriers will balance the concentration of Aβ in the body. (C) In AD context, astrocytes will become reactive astrocytes, which will disturb the BBB, decreasing the number of RAGE, LRPs, and NEP, and eventually causing the accumulation of Aβ, forming a vicious circle. (D) MSCs treatment can turn reactive astrocytes into normal astrocytes, ameliorate the damage of blood vessels, and therefore cure the disease to some extent. (E–G) Changes of neuroinflammation. (E) In physiological conditions, both astrocytes and microglia will secrete proper amount of inflammatory factors such as TNF-α and IL-1β, maintain the homeostasis in the body. (F) In AD context, either astrocytes or microglia will become reactive, which will secrete much more TNF-α and IL-1β. Accumulation of Aβ and reactive microglia will also stimulate astrocytes, aggravating astrogliosis. (G) MSCs treatment can turn reactive astrocytes into normal astrocytes, ameliorate the inflammatory context. (H–J) Changes of glutamatergic synapses. (H) In physiological conditions, astrocytes and neurons form tripartite, regulating the release and clearance of glutamate. (I) In AD context, the number of glutamate-related receptors will decrease, especially those on the astrocytes, disturbing the clearance of glutamate. (J) MSCs treatment can increase the number of some receptors, and rebalance the glutamate homeostasis. (K–M) Changes of GABAergic synapses. (K) In physiological conditions, GABA is regulated by vGAT. (L) In AD context, the amount of vGAT will decrease, disturbing the GABA homeostasis. (M) MSCs treatment can increase the number vGAT, rebalancing the number of GABA in the synapses. (N–P) MSCs can ameliorate the damage to neurons through astrocytes. (N) In physiological conditions, astrocytes and neurons are together regulating the activities in the brain. And the neurotrophic factors like BDNF, secreted by astrocytes, can support the growth of neurons. (O) In AD context, astrocytes will become reactive, there will be less BDNF, and some neurons will die. (P) After MSCs treatment, MSCs can turn reactive astrocytes into astrocytes, which can secret neurotrophics like BDNF to support neurons.