Invited ReviewInflammation in Alzheimer’s disease: Lessons learned from microglia-depletion models
Introduction
Microglia are the brain’s resident immune cells, comprising approximately 5–12% of all cells found in the brain. They function as the brain’s first line of defense to protect the CNS from injury and invading pathogens. Originally presumed to be “resting”, microglia in the healthy adult brain are highly dynamic, surveying the entire brain parenchyma every 24 h (Nimmerjahn et al., 2005). In this “surveying” state, microglia exhibit a ramified morphology and serve to support neuronal function and health via physical and biochemical interactions. Upon detection of an insult, microglia respond by becoming activated. This process may involve the migration to and proliferation of these cells at the site of the insult, as well as dramatic transformation into an amoeboid morphology, depending on the type and extent of the insult. Activated microglia produce and secrete several proinflammatory mediators, including tumor necrosis factor-α (TNFα), interleukin (IL)-6, and nitric oxide (NO), all of which can confer neurotoxicity (Akiyama et al., 2000). Neuroimmune regulatory proteins (NiReg) modulate the microglia-mediated immune response to resolve the inflammatory process (Hoarau et al., 2011), which then promotes tissue repair through the secretion of several neurotrophic factors, including insulin-like growth factor 1 (IGF-1), brain-derived neurotrophoc factor (BDNF), transforming-growth factor-β (TGF-β), and nerve growth factor (NGF) (Polazzi and Monti, 2010). In acute inflammatory events, the pro-inflammatory response resolves and microglia continue their surveillance of the brain parenchyma. However, in neurodegenerative disease, the equilibrium between microglial surveillance and activation is disturbed, creating a feedforward loop that results in a chronic neuroinflammatory state, promoting inflammation and tissue atrophy. Although astrocytes also participate in and propagate the neuroinflammatory environment in AD, for the purposes of this review, the focus will remain on microglia-mediated inflammation in AD pathogenesis. Here, we briefly review the various implications of microglia and other myeloid cells in neurodegeneration and discuss current methods that allow for investigations into the biology of microglia in AD.
Section snippets
Phagocytosis
One of the more extensively studied functions of microglia in the brain is their role in clearance via phagocytosis, by which these cells both protect the brain from invading pathogens as well as remove cellular debris from the neural environment. Aside from the clearance of cellular debris, microglia may also phagocytose viable neurons in a process known as “phagoptosis”, which specifically targets senescent or damaged cells (Brown and Neher, 2014). For this reason, proper degradation of
AD pathophysiology
In contrast to the beneficial roles of microglia in the homeostatic brain, the activation of these cells is heavily implicated in the progression of several neurodegenerative diseases, including AD. AD is a progressive neurodegenerative disease characterized by the extracellular deposition of Aβ-associated plaques and intracellular tau-associated neurofibrillary tangles. It is also one of the most common forms of dementia, affecting roughly 10% of the population aged 65, and up to 50% of people
Microglial dysfunction and inflammation in AD
Over one hundred years ago, Alois Alzheimer first identified the presence of plaque-associated microglia in post-mortem brains (Alzheimer et al., 1995) and since then, activated microglia have been considered a key feature of AD pathology. In the AD brain, the number and size of microglia directly increase proportionally to the size of the plaques (Wegiel et al., 2001) and proliferate in the vicinity of plaques leading to the accumulation of these cells at amyloid deposits (Frautschy et al.,
Cognitive dysfunction mediated by synaptic and neuronal loss
Modulation of microglial function in AD has been repeatedly shown to improve cognitive function (i.e. (Parachikova et al., 2010, Yamanaka et al., 2012)), indicating that chronically reactive microglia are promoting the cognitive decline that occurs in the disease. In accordance with this, chronically eliminating microglia in 5xfAD mice improved hippocampal dependent-memory, as assessed by contextual fear conditioning (Spangenberg et al., 2016). Notably, synapse degeneration is the best
Contribution of peripheral myeloid cells in Aβ clearance
In certain murine models, such as repeated social defeat and irradiation conditioning in AD, peripheral myeloid cells are capable of crossing the BBB to mediate differential effects in the brain (Mildner et al., 2007, Wohleb et al., 2013). It is theorized that peripherally-derived myeloid cells possess a greater capacity to phagocytose amyloid than endogenous microglia, as reducing their association with plaques (Jay et al., 2015) or restricting the infiltration of myeloid cells into the brain (
Microglial maintenance of tau pathology
In the healthy brain, tau proteins are abundant in the CNS and function to stabilize microtubules in axons. However, in a disease state, such as AD, the binding of tau proteins to microtubules is interrupted, leading to high levels of free tau which is ultimately converted to aggregated and fibrillized tau (Kuret et al., 2005). Microglial activation is implicated as a driver of this pathological change, as it was shown to precede the accumulation of neurofibrillary tangles in a tauopoathy mouse
Anti-inflammatories to alleviate AD
Increasing evidence indicates that inflammation is a major element in the promotion of progressive CNS damage. Approaches to mitigate microglia-mediated neuroinflammation in neurodegenerative disease have long been developed, with PPARy agonists, statins, flavonoids, COX2 inhibitors, minocycline, and glatiramer acetate showing positive effects on mouse models of AD or patients enrolled in clinical trials (Zipp and Aktas, 2006). Delivery of an IL-1 receptor antagonist via injection of neural
Acute inflammation mediated by microglia
Although it is accepted that chronic neuroinflammation is detrimental to the brain, acute inflammation may serve an important function for tissue repair and angiogenesis (Varin and Gordon, 2009). Therefore, the timing of microglial modulation is critical, as these cells can have both harmful and beneficial effects in the brain during inflammatory events. In a genetic hippocampal lesion model, we sought to determine the effects of eliminating microglia during different phases of a neuronal
Conclusions – net impact of microglia in AD
Together, much remains to be determined about the role of microglia in AD. In development, these cells serve to shape neuronal connectivity through refinement of extranumerous synapses to establish a functional network, and importantly, microglia continue to sculpt the synaptic landscape throughout adulthood. However, the ways in which their function changes in AD and to what extent requires further experimentation. Whether microglia are exerting neuroprotective or neurodegenerative effects in
Conflict of interest
The authors E.E.S and K.N.G have no conflicting financial interests.
Acknowledgments
This work was generously funded by the National Institutes of Health under awards 1R01NS083801 (NINDS) and P50 AG016573 (NIA) to K.N.G., in addition to the American Federation of Aging Research to K.N.G., the Alzheimer’s Association to K.N.G., and a Glenn Foundation Award to K.N.G.
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