The evolving dialogue of microglia and neurons in Alzheimer’s disease: microglia as necessary transducers of pathology

The understanding of the contribution of microglial cells to the onset and/or progression chronic neurodegenerative diseases is key to identify disease-modifying therapies, given the strong neuroimmune component of these disorders. In this review, we dissect the different pathways by which microglia can affect, directly or indirectly, neuronal function and dysfunction associated with diseases like Alzheimer’s. We here present the rationale for proposing a model to explain the contribution of microglia to the pathophysiology of Alzheimer’s disease, defining microglial cells as necessary transducers of pathology and ideal targets for intervention. acute cognitive . Moreover, injection of LPS during brain development enhances microglial activity and results in increased levels of proinflammatory cytokines IL-1 β , IL-6 and TNF α . Altogether these studies suggest that microglial priming can affect brain development and, later, the onset and progression of neurodegenerative diseases.


Introduction
Microglia and neurons participate in a dynamic bi-directional communication that is essential for brain development and homeostasis, with its disturbance potentially contributing to disease. The two-way communication between these cell types includes neurons modulating microglial activation states by the release of factors such as chemokines, neurotransmitters and purinergic signalling, as well as microglia influencing neuronal function and connectivity either by direct physical contact with neuronal elements or by releasing paracrine signals.
Microglia originate from yolk-sac derived progenitors that invade the brain during In order to maintain brain homeostasis, intercellular communications must be tightly controlled, and a dysregulation of this intercommunication is known to occur in disease. Many brain diseases are characterized by inflammatory responses controlled by microglia (Gomez-Nicola and Perry 2015), which disturb physiological interactions between microglia and neurons and could directly contribute to neurodegeneration via the production of neurotoxic substances. In this review, we discuss changes in the microglia-neuron cross-talk in Alzheimer's disease (AD) and how these changes might contribute to neurodegeneration, placing microglia as necessary effectors of AD-related pathology.

Direct microglia-neuron interactions in AD
Microglia are the brain's main resident immune cells and remain "immunologically silent" with limited immune function in the healthy brain. Microglia are believed to be kept in this homeostatic state by neuronal immunomodulators, such as CX3CL1 and CD200, which bind to their cognate receptors present on microglia. This intercommunication via inhibitory signals seems to be dysregulated in neurodegenerative disease (Sheridan and Murphy 2013). CD200 is a type I membrane glycoprotein present on neurons in the rodent brain and interacts with the CD200 receptor (CD200R) which is a myeloid cell receptor found on microglia In the healthy brain microglia-to-neuron crosstalk is best illustrated by the ability of microglia to establish direct physical contacts with neuronal elements, participating in shaping developing neuronal circuitries through synaptic pruning. Upon brain disease such as AD, microglia induce an inflammatory response that develops alongside neuropathological features, likely influencing neuronal integrity and function and, consequently, contributing to neurodegeneration. Some of the first indications that activated microglia produce neurotoxic molecules that can directly These studies suggest that microglia take up tau, regardless of the aggregation state of the protein, and support the notion that these cells play a key role in its clearance or its propagation, acting as necessary intermediates of pathology.

Microglia as necessary effectors of Aβ-mediated pathology in AD
It is well described now that, together with the deposition of NFTs and Aβ plaques,

2016).
Increasing evidence has correlated priming microglia with exacerbated disease (Fig.   1). The phenomenon of priming is characterized by effect of a pre-exposition of microglia to stress that will further potentiate the neuroinflammatory response to a

Phenotypic diversity of microglia in AD: different roles for different cells?
The study of the role of microglia in AD has recently incorporated a regional and to the pathology, discussed in previous sections, which targeting may provide a beneficial impact in AD.

Conclusion
Increasing evidence suggest an essential, but bivalent, role of microglia in the development and progression of neurodegenerative diseases. The activation of microglia has been associated with neuroprotective effects by clearing cell debris, phagocytosing dead cells and releasing neurotrophic factors. On the other hand, microglial activation has also been correlated with chronic neuroinflammation contributing to neurodegeneration. Altogether, these studies confirm the dual role of microglia in the development and the progression of the disease and reveal the complexity of the factors regulating the balance of beneficial vs detrimental effects of microglia in neurodegenerative diseases. Despite its complex and dual role, it becomes obvious that microglia are a relevant target in neurodegenerative diseases, as neuroinflammation is involved in neurodegeneration in a direct or indirect way ( Fig. 1). The remaining question is: which are the key pathways to target and during which time window in the disease?. We conclude that, in the future, a systematic probing of the mechanistic contribution of the individual molecular determinants of disease-associated microglia will provide a solid avenue into the pre-clinical domain.
This will allow a deep and comprehensive evaluation of the model proposed in here, by which microglia are necessary transducers of AD pathology. Progressing the field into this domain will not only expand our understanding of microglia, but more importantly will open new avenues into devising the, long-due, disease-modifying therapies that provide a benefit to patients.