Neuronal and glial cell interaction is essential for synaptic homeostasis and may be affected in Alzheimer’s disease (AD). We measured cerebrospinal fluid (CSF) neuronal and glia markers along the AD continuum, to reveal putative protective or harmful stage-dependent patterns of activation. We included healthy controls (n = 36) and Aβ-positive (Aβ+) cases (as defined by pathological CSF amyloid beta 1-42 (Aβ42)) with either subjective cognitive decline (SCD, n = 19), mild cognitive impairment (MCI, n = 39), or AD dementia (n = 27). The following CSF markers were measured: a microglial activation marker—soluble triggering receptor expressed on myeloid cells 2 (sTREM2), a marker of microglial inflammatory reaction—monocyte chemoattractant protein-1 (MCP-1), two astroglial activation markers—chitinase-3-like protein 1 (YKL-40) and clusterin, a neuron-microglia communication marker—fractalkine, and the CSF AD biomarkers (Aβ42, phosphorylated tau (P-tau), total tau (T-tau)). Using ANOVA with planned comparisons, or Kruskal-Wallis tests with Dunn’s pairwise comparisons, CSF levels were compared between clinical groups and between stages of biomarker severity using CSF biomarkers for classification based on amyloid pathology (A), tau pathology (T), and neurodegeneration (N) giving rise to the A/T/N score. Compared to healthy controls, sTREM2 was increased in SCD (p < .01), MCI (p < .05), and AD dementia cases (p < .001) and increased in AD dementia compared to MCI cases (p < .05). MCP-1 was increased in MCI (p < .05) and AD dementia compared to both healthy controls (p < .001) and SCD cases (p < .01). YKL-40 was increased in dementia compared to healthy controls (p < .01) and MCI (p < .05). All of the CSF activation markers were increased in subjects with pathological CSF T-tau (A+T−N+ and A+T+N+), compared to subjects without neurodegeneration (A−T−N− and A+T−N−). Microglial activation as indicated by increased sTREM2 is present already at the preclinical SCD stage; increased MCP-1 and astroglial activation markers (YKL-40 and clusterin) were noted only at the MCI and AD dementia stages, respectively, and in Aβ+ cases (A+) with pathological T-tau (N+). Possible different effects of early and later glial activation need to be explored.

/pdf/glial-activation-and-inflammation-along-the-alzheimer-s-4utzz0py3g.pdf

Glial activation and inflammation along the Alzheimer's disease continuum.

Neuroinflammation is a key part of the etio-pathogenesis of Alzheimer's disease (AD). We tested the relationship between neuroinflammation and the disruption of functional connectivity in large-scale networks, and their joint influence on cognitive impairment. We combined [11C]PK11195 positron emission tomography (PET) and resting-state functional magnetic resonance imaging (rs-fMRI) in 28 patients (12 females/16 males) with clinical diagnosis of probable AD or mild cognitive impairment with positive PET biomarker for amyloid, and 14 age-, sex-, and education-matched healthy controls (8 females/6 males). Source-based "inflammetry" was used to extract principal components of [11C]PK11195 PET signal variance across all participants. rs-fMRI data were preprocessed via independent component analyses to classify neuronal and non-neuronal signals. Multiple linear regression models identified sources of signal covariance between neuroinflammation and brain connectivity profiles, in relation to the diagnostic group (patients, controls) and cognitive status.Patients showed significantly higher [11C]PK11195 binding relative to controls, in a distributed spatial pattern including the hippocampus, frontal, and inferior temporal cortex. Patients with enhanced loading on this [11C]PK11195 binding distribution displayed diffuse abnormal functional connectivity. The expression of a stronger association between such abnormal connectivity and higher levels of neuroinflammation correlated with worse cognitive deficits.Our study suggests that neuroinflammation relates to the pathophysiological changes in network function that underlie cognitive deficits in Alzheimer's disease. Neuroinflammation, and its association with functionally-relevant reorganization of brain networks, is proposed as a target for emerging immunotherapeutic strategies aimed at preventing or slowing the emergence of dementia.SIGNIFICANCE STATEMENT Neuroinflammation is an important aspect of Alzheimer's disease (AD), but it was not known whether the influence of neuroinflammation on brain network function in humans was important for cognitive deficit. Our study provides clear evidence that in vivo neuroinflammation in AD impairs large-scale network connectivity; and that the link between neuro inflammation and functional network connectivity is relevant to cognitive impairment. We suggest that future studies should address how neuroinflammation relates to network function as AD progresses, and whether the neuroinflammation in AD is reversible, as the basis of immunotherapeutic strategies to slow the progression of AD.

https://www.jneurosci.org/content/jneuro/39/36/7218.full.pdf

Neuroinflammation and Functional Connectivity in Alzheimer's Disease: Interactive Influences on Cognitive Performance

Alzheimer’s disease (AD) is a debilitating neurological disorder, and currently, there is no cure for it. Several pathologic alterations have been described in the brain of AD patients, but the ultimate causative mechanisms of AD are still elusive. The classic hallmarks of AD, including amyloid plaques (Aβ) and tau tangles (tau), are the most studied features of AD. Unfortunately, all the efforts targeting these pathologies have failed to show the desired efficacy in AD patients so far. Neuroinflammation and impaired autophagy are two other main known pathologies in AD. It has been reported that these pathologies exist in AD brain long before the emergence of any clinical manifestation of AD. Microglia are the main inflammatory cells in the brain and are considered by many researchers as the next hope for finding a viable therapeutic target in AD. Interestingly, it appears that the autophagy and mitophagy are also changed in these cells in AD. Inside the cells, autophagy and inflammation interact in a bidirectional manner. In the current review, we briefly discussed an overview on autophagy and mitophagy in AD and then provided a comprehensive discussion on the role of these pathways in microglia and their involvement in AD pathogenesis.

Alzheimer's Disease Pathogenesis: Role of Autophagy and Mitophagy Focusing in Microglia.

Eriodictyol, a natural flavonoid mainly distributed in citrus fruits and peanut, has been well-documented with possession of excellent anti-inflammatory, antioxidant, and anticancer bioactivities This work focus on the protective effects of eriodictyol on LPS-induced neuroinflammation, amyloidogenesis, cognitive impairment, and the potential mechanisms involved Behavioral tests and histological examinations showed that eriodictyol significantly prevented the memory and neuronal damage triggered by LPS Consistently, eriodictyol (100 mg/kg) reduced the formation of Aβ1-42 by 2837 ± 1671 pg/mL compared to the LPS group In addition, high dose eriodictyol (100 mg/kg) also equilibrated the cholinergic system via suppressing AChE activity (01996 ± 00831 U/mgprot) and elevating ChAT activity (4181 ± 2472 U/g) as well as ACh level (5093 ± 3531 μg/mgprot) compared to the LPS group Western blot results indicated that compared to the LPS group, eriodictyol suppressed LPS-induced glial overactivation (8429% ± 2721%) and regulated inflammatory mediators and cytokines by inhibiting the NF-κB and MAPK pathways These results indicated that eriodictyol alleviated amyloidogenesis and memory impairment triggered by LPS via inhibiting TLR4, MAPKs, and PI3K/Akt, and activating Sirt1 pathways and thus blocking downstream translocation of NF-κB, which offers a potential nutritional preventive strategy for neuroinflammation diseases such as Alzheimer's disease (AD)

Eriodictyol Attenuates LPS-Induced Neuroinflammation, Amyloidogenesis, and Cognitive Impairments via the Inhibition of NF-κB in Male C57BL/6J Mice and BV2 Microglial Cells

Overweight and obesity are now considered a worldwide pandemic and a growing public health problem with severe economic and social consequences. Adipose tissue is an organ with neuroimmune-endocrine functions, which participates in homeostasis. So, adipocyte hypertrophy and hyperplasia induce a state of chronic inflammation that causes changes in the brain and induce neuroinflammation. Studies with obese animal models and obese patients have shown a relationship between diet and cognitive decline, especially working memory and learning deficiencies. Here we analyze how obesity-related peripheral inflammation can affect central nervous system physiology, generating neuroinflammation. Given that the blood-brain barrier is an interface between the periphery and the central nervous system, its altered physiology in obesity may mediate the consequences on various cognitive processes. Finally, several interventions, and the use of natural compounds and exercise to prevent the adverse effects of obesity in the brain are also discussed.

/pdf/the-obese-brain-mechanisms-of-systemic-and-local-3qe257st.pdf

The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit

Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease of central nervous system (CNS). Nowadays, increasing evidence suggests that immune system plays a significant role in the mechanisms of AD's onset and progression. Microglia, the main participator in the immune system of CNS, is always regarded as a protector of our brain in a healthy state and also has a beneficial role in maintaining the homeostasis of CNS microenvironment. However, chronic and sustained stimulation can push microglia into the state termed priming. Primed microglia can induce the production of amyloid β (Aβ), tau pathology, neuroinflammation and reduce the release of neurotrophic factors, resulting in loss of normal neurons in quantity and function that has immense relationship with AD. The therapeutic strategies mainly aimed at modulating the microenvironment and microglial activity in CNS to delay progression and alleviate pathogenesis of AD. Overall, in this review, we highlight the mechanism of microglial priming, and discuss the profound relationship between microglial priming and AD. Besides, we also pay attention to the therapeutic strategies targeting at microglial priming.

/pdf/microglial-priming-in-alzheimer-s-disease-2a0a5opavm.pdf

Microglial priming in Alzheimer's disease.

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Microglial priming in Alzheimer's disease.