As the median age of the population increases, the number of individuals with Alzheimer's disease (AD) and the associated socio-economic burden are predicted to worsen. While aging and inherent genetic predisposition play major roles in the onset of AD, lifestyle, physical fitness, medical condition, and social environment have emerged as relevant disease modifiers. These environmental risk factors can play a key role in accelerating or decelerating disease onset and progression. Among known environmental risk factors, chronic exposure to various metals has become more common among the public as the aggressive pace of anthropogenic activities releases excess amount of metals into the environment. As a result, we are exposed not only to essential metals, such as iron, copper, zinc and manganese, but also to toxic metals including lead, aluminum, and cadmium, which perturb metal homeostasis at the cellular and organismal levels. Herein, we review how these metals affect brain physiology and immunity, as well as their roles in the accumulation of toxic AD proteinaceous species (i.e., β-amyloid and tau). We also discuss studies that validate the disruption of immune-related pathways as an important mechanism of toxicity by which metals can contribute to AD. Our goal is to increase the awareness of metals as players in the onset and progression of AD.

As the understanding of immune responses in Alzheimer's disease (AD) is in its early phases, there remains an urgency to identify the cellular and molecular processes driving chronic inflammation. In AD, a subpopulation of astrocytes acquires a neurotoxic phenotype which prompts them to lose typical physiological features. While the underlying molecular mechanisms are still unknown, evidence suggests that myeloid differentiation primary response 88 (MyD88) adaptor protein may play a role in coordinating these cells' immune responses in AD. Herein, we combined studies in human postmortem samples with a conditional genetic knockout mouse model to investigate the link between MyD88 and astrocytes in AD. In silico analyses of bulk and cell-specific transcriptomic data from human postmortem brains demonstrated an upregulation of MyD88 expression in astrocytes in AD versus non-AD individuals. Proteomic studies revealed an increase in glial fibrillary acidic protein in multiple brain regions of AD subjects. These studies also showed that although overall MyD88 steady-state levels were unaffected by AD, this protein was enriched in astrocytes near amyloid plaques and neurofibrillary tangles. Functional studies in mice indicated that the deletion of astrocytic MyD88 protected animals from the acute synaptic toxicity and cognitive impairment caused by the intracerebroventricular administration of β-amyloid (Aβ). Lastly, unbiased proteomic analysis revealed that loss of astrocytic MyD88 resulted in altered astrocyte reactivity, lower levels of immune-related proteins, and higher expression of synaptic-related proteins in response to Aβ. Our studies provide evidence of the pivotal role played by MyD88 in the regulation of astrocytes response to AD.

Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD. In silico analysis of bulk and cell-specific transcriptomic data revealed the association of NF-κB and astrocytes in AD. Confocal studies validated the higher level of p50 NF-κB and phosphorylated-p65 NF-κB in glial fibrillary acidic protein (GFAP)⁺-astrocytes in AD versus non-AD subjects. In the healthy mouse brain, chronic activation of astrocytic NF-κB disturbed the proteomic milieu, causing a loss of mitochondrial-associated proteins and the rise of inflammatory-related proteins. Sustained NF-κB signaling also led to microglial reactivity, production of pro-inflammatory mediators, and buildup of senescence-related protein p16^INK4A in neurons. However, in an AD mouse model, NF-κB inhibition accelerated β-amyloid and tau accumulation. Molecular biology studies revealed that astrocytic NF-κB activation drives the increase in GFAP and inflammatory proteins and aquaporin-4, a glymphatic system protein that assists in mitigating AD. Our investigation uncovered fundamental mechanisms by which NF-κB enables astrocytes' neuroprotective and neurotoxic responses in the brain.