Synapse loss is the strongest correlate for cognitive decline in Alzheimer's disease. The mechanisms underlying synapse loss have been extensively investigated using mouse models expressing genes with human familial Alzheimer's disease mutations. In this review, we summarize how multiphoton in vivo imaging has improved our understanding of synapse loss mechanisms associated with excessive amyloid in the living animal brain. We also discuss evidence obtained from these imaging studies for the role of cell-intrinsic calcium dyshomeostasis and cell-extrinsic activities of microglia, which are the immune cells of the brain, in mediating synapse loss.
There are many types of intercellular communication, and extracellular vesicles are one of the important forms of this. They are released by a variety of cell types, are heterogeneous, and can roughly be divided into microvesicles and exosomes according to their occurrence and function. Of course, exosomes do not just play a role in cell-to-cell communication. In the nervous system, exosomes can participate in intercellular communication, maintain the myelin sheath, and eliminate waste. Similarly, exosomes in the brain can play a role in central nervous system diseases, such as stroke, Alzheimer’s disease (AD), Parkinson’s disease (PD), prion disease, and traumatic encephalopathy (CTE), with both positive and negative effects (such as the transfer of misfolded proteins). Exosomes contain a variety of key bioactive substances and can therefore be considered as a snapshot of the intracellular environment. Studies have shown that exosomes from the central nervous system can be found in cerebrospinal fluid and peripheral body fluids, and that their contents will change with disease occurrence. Because exosomes can penetrate the blood brain barrier (BBB) and are highly stable in peripheral circulation, they can protect disease-related molecules well and therefore, using exosomes as a biomarker of central nervous system diseases is an attractive prospect as they can be used to monitor disease development and enable early diagnosis and treatment optimization. In this review, we discuss the current state of knowledge of exosomes, and introduce their pathophysiological roles in different diseases of the central nervous system as well as their roles and applications as a viable pathological biomarker.
Brain derived neurotrophic factor (BDNF) is well recognized for its neuroprotective functions, via activation of its high affinity receptor, tropomysin related kinase B (TrkB). In addition, BDNF/TrkB neuroprotective functions can also be elicited indirectly via activation of adenosine 2A receptors (A2aRs), which in turn transactivates TrkB. Evidence suggests that alterations in BDNF/TrkB, including TrkB transactivation by A2aRs, can occur in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Although enhancing BDNF has been a major goal for protection of dying motor neurons (MNs), this has not been successful. Indeed, there is emerging in vitro and in vivo evidence suggesting that an upregulation of BDNF/TrkB can cause detrimental effects on MNs, making them more vulnerable to pathophysiological insults. For example, in ALS, early synaptic hyper-excitability of MNs is thought to enhance BDNF-mediated signaling, thereby causing glutamate excitotoxicity, and ultimately MN death. Moreover, direct inhibition of TrkB and A2aRs has been shown to protect MNs from these pathophysiological insults, suggesting that modulation of BDNF/TrkB and/or A2aRs receptors may be important in early disease pathogenesis in ALS. This review highlights the relevance of pathophysiological actions of BDNF/TrkB under certain circumstances, so that manipulation of BDNF/TrkB and A2aRs may give rise to alternate neuroprotective therapeutic strategies in the treatment of neural diseases such as ALS.
Synapse loss is an early feature shared by many neurodegenerative diseases, and it represents the major correlate of cognitive impairment. Recent studies reveal that microglia and astrocytes play a major role in synapse elimination, contributing to network dysfunction associated with neurodegeneration. Excitatory and inhibitory activity can be affected by glia-mediated synapse loss, resulting in imbalanced synaptic transmission and subsequent synaptic dysfunction. Here, we review the recent literature on the contribution of glia to excitatory/inhibitory imbalance, in the context of the most common neurodegenerative disorders. A better understanding of the mechanisms underlying pathological synapse loss will be instrumental to design targeted therapeutic interventions, taking in account the emerging roles of microglia and astrocytes in synapse remodeling.