Gut inflammation associated with age and Alzheimer's disease pathology: a human cohort study.

Age-related disease may be mediated by low levels of chronic inflammation ("inflammaging"). Recent work suggests that gut microbes can contribute to inflammation via degradation of the intestinal barrier. While aging and age-related diseases including Alzheimer's disease (AD) are linked to altered microbiome composition and higher levels of gut microbial components in systemic circulation, the role of intestinal inflammation remains unclear. To investigate whether greater gut inflammation is associated with advanced age and AD pathology, we assessed fecal samples from older adults to measure calprotectin, an established marker of intestinal inflammation which is elevated in diseases of gut barrier integrity. Multiple regression with maximum likelihood estimation and Satorra-Bentler corrections were used to test relationships between fecal calprotectin and clinical diagnosis, participant age, cerebrospinal fluid biomarkers of AD pathology, amyloid burden measured using 11C-Pittsburgh compound B positron emission tomography (PiB PET) imaging, and performance on cognitive tests measuring executive function and verbal learning and recall. Calprotectin levels were elevated in advanced age and were higher in participants diagnosed with amyloid-confirmed AD dementia. Additionally, among individuals with AD dementia, higher calprotectin was associated with greater amyloid burden as measured with PiB PET. Exploratory analyses indicated that calprotectin levels were also associated with cerebrospinal fluid markers of AD, and with lower verbal memory function even among cognitively unimpaired participants. Taken together, these findings suggest that intestinal inflammation is linked with brain pathology even in the earliest disease stages. Moreover, intestinal inflammation may exacerbate the progression toward AD.

Modulation of Glial Function in Health, Aging, and Neurodegenerative Disease.

In the central nervous system (CNS), glial cells, such as microglia and astrocytes, are normally associated with support roles including contributions to energy metabolism, synaptic plasticity, and ion homeostasis. In addition to providing support for neurons, microglia and astrocytes function as the resident immune cells in the brain. The glial function is impacted by multiple aspects including aging and local CNS changes caused by neurodegeneration. During aging, microglia and astrocytes display alterations in their homeostatic functions. For example, aged microglia and astrocytes exhibit impairments in the lysosome and mitochondrial function as well as in their regulation of synaptic plasticity. Recent evidence suggests that glia can also alter the pathology associated with many neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's disease (PD). Shifts in the microbiome can impact glial function as well. Disruptions in the microbiome can lead to aberrant microglial and astrocytic reactivity, which can contribute to an exacerbation of disease and neuronal dysfunction. In this review, we will discuss the normal physiological functions of microglia and astrocytes, summarize novel findings highlighting the role of glia in aging and neurodegenerative diseases, and examine the contribution of microglia and astrocytes to disease progression.

The Role of Microglia and the Nlrp3 Inflammasome in Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent form of late-onset dementia. AD affects the health of millions of people in the United States and worldwide. Currently, there are no approved therapies that can halt or reverse the clinical progression of AD. Traditionally, AD is characterized first by the appearance of amyloid-ß (Aß) plaques followed by the formation of intraneuronal neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau). These lesions are linked to synapse loss and eventual cognitive impairment. Additionally, microgliosis is consistently found in regions of the brain with AD pathology. The role of microglia in AD onset and progression remains unclear. Several recent reports indicate that the assembly of the multi-protein complex known as the NOD, LRR, and pyrin-domain containing 3 (Nlrp3) inflammasome by microglia results in apoptosis spec-like protein containing a CARD (Asc) spec formation, which then nucleates new Aß plaques, thus amplifying Aß-associated pathology. NFTs can also activate the Nlrp3 inflammasome leading to enhanced tau-associated pathology. Here, we will review the role of microglia and the activation of the inflammasome in the innate immune response to AD.

Regenerative capacity in the lamprey spinal cord is not altered after a repeated transection.

The resilience of regeneration in vertebrates is not very well understood. Yet understanding if tissues can regenerate after repeated insults, and identifying limitations, is important for elucidating the underlying mechanisms of tissue plasticity. This is particularly challenging in tissues, such as the nervous system, which possess a large number of terminally differentiated cells and often exhibit limited regeneration in the first place. However, unlike mammals, which exhibit very limited regeneration of spinal cord tissues, many non-mammalian vertebrates, including lampreys, bony fishes, amphibians, and reptiles, regenerate their spinal cords and functionally recover even after a complete spinal cord transection. It is well established that lampreys undergo full functional recovery of swimming behaviors after a single spinal cord transection, which is accompanied by tissue repair at the lesion site, as well as axon and synapse regeneration. Here we begin to explore the resilience of spinal cord regeneration in lampreys after a second spinal transection (re-transection). We report that by all functional and anatomical measures tested, lampreys regenerate after spinal re-transection just as robustly as after single transections. Recovery of swimming, synapse and cytoskeletal distributions, axon regeneration, and neuronal survival were nearly identical after spinal transection or re-transection. Only minor differences in tissue repair at the lesion site were observed in re-transected spinal cords. Thus, regenerative potential in the lamprey spinal cord is largely unaffected by spinal re-transection, indicating a greater persistent regenerative potential than exists in some other highly regenerative models. These findings establish a new path for uncovering pro-regenerative targets that could be deployed in non-regenerative conditions.