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Neuroinflammation and selective vulnerability of the Entorhinal Cortex in models of neurodegeneration

Within the medial temporal lobe memory system, the main pathway for the transmission of sensory information to the hippocampus is represented by the entorhinal cortex (EC). The medial temporal lobe is also central to the pathophysiology of AD since histopathology suggests it is affected during the earliest phases of the disease. Specifically, abnormal protein aggregates such as amyloid plaques and neurofibrillary tangles have been observed to accumulate in this region and the density of these lesions correlates with AD severity. Within the medial temporal lobe, the distribution of the typical AD histopathological findings follows a specific progression, first beginning in layer II of the EC and then spreading to the hippocampal formation. The selective vulnerability of EC neurons might be the result of a particular susceptibility to microenviromental factors, such as increased Aβlevels and vascular injury that interact with molecular peculiarities of these cells. We have investigated the effects of Aβon basal synaptic transmission and plasticity in the EC layer II intracortical connections. Our studies can be summarized as follow:

a) Role of microglial and neuronal RAGE in Aβ mediated cortical synaptic dysfunction.

Receptor for Advanced Glycation Endproducts (RAGE) functions as cell surface binding sites for Aβ. We investigated the role of cell-specific activation of RAGE (microglial vs. neuronal) in Aβ-dependent synapticdysfunction using inhibitory antibodies to RAGE, RAGE knock-out mice (RAGE-KO) and mice expressing adefective form of RAGE targeted to neurons (DN-RAGE) or microglia (DNMSR). We found that nanomolar Aβimpairs LTP in the EC layer II, through neuronal RAGE-mediated activation of p38 MAPK (Origlia et al., JNeurosci 2008). This results was confirmed in a different cortical area, the visual cortex (Origlia et al., J Alzh Dis2009). Remarkably, accumulation of Aβ causes the activation of microglia and release of proinflammatorycytokines. We raised the key question of whether brain neuroinflammation is involved in progressive synaptic and cognitive deficits induced by Aβ load. We found that high Aβ concentrations induce specific phosphorylation of p38 MAPK and JNK in neuronal and non-neuronal cells that depend on microglial RAGE activation along with the proinflammatory cytokine, Interleukin-1β(IL-1β). IL-1βwould consequently affect basal synaptic transmission and LTD by regulating glutamate receptors function (Origlia et al., J Neurosci 2010; Fig.1).

fig.1


These findings contributed to the identification of a specific inflammatory pathway activated by high Aβ levels that establishes a self-maintained neuronal-microglial loop leading to synaptic dysfunction. Thus, progression of synaptic dysfunction by Aβ is concentration dependent, possibly corresponding to cognitive decline induced by its accumulation during AD. We confirmed the temporal profile of Aβ-dependent synaptic dysfunction in mutant human APP transgenic mice (J20 line), characterized by progressive accumulation of Aβ in different brain areas (Criscuolo et al., 2017).

b). Vascular and trophic factors implicated in Aβ-dependent EC dysfunction

Hypoxia may be a cause of the progressive neuronal alterations in AD. However, a causal relationship between oxygen deficiency and AD at the cellular and molecular level has not been established. Recent understanding has confirmed that RAGE plays a role in the pathogenesis of neurodegenerative disorders, including AD. Moreover, RAGE is up-regulated in response to brain hypoxia/ischemia and its activation contributes to inflammation and ischemic brain damage. We addressed the hypothesis that transient ischemia facilitates EC synaptic impairment induced by Aβ signaling through RAGE. We demonstrated that transient brain hypoxia/ischemia functions as a trigger for neuronal perturbation induced by progressive accumulation of Aβ and that RAGE could be an important factor in accelerating synaptic dysfunction (Fig.2).

fig.2


Our findings highlighted RAGE as a new molecular link between vascular pathology and AD (Origlia et al., J Neurosci, 2014). Finally, we focused on alternative strategies to interfere with Aβ/RAGE signaling in the attempt to reduce synaptic dysfunction. In particular, we investigated the role of BDNF as neuroprotective agent capable of preventing Aβ synaptotoxicity. BDNF is an endogenous neurotrophic factor of the NGF family (neurotrophins) that controls neuronal development and brain functional connectivity, particularly in brain regions such as the EC and hippocampus. BDNF and its receptors change in AD, with BDNF level being reduced in the EC. The reduction of BDNF level seen in AD could cripple the EC in two ways: insufficient BDNF would affect synaptic strength and reduced BDNF would make neurons more vulnerable to Aβ toxicity. Thus, new treatments based on neuroprotection by BDNF might open new horizons, as far as the research strategy and the potential for therapeutic transfer. We demonstrated that BDNF controls synaptic function in EC and is capable of preventing synaptic dysfunction induced by Aβ/RAGE interaction (Criscuolo et al., Neurobiol of Aging, 2015)