Hippocampal TMEM55B overexpression in the 5XFAD mouse model of Alzheimer's disease.

Dysfunction of the endosomal-lysosomal network is a notable feature of Alzheimer's disease (AD) pathology. Dysfunctional endo-lysosomal vacuoles accumulate in dystrophic neurites surrounding amyloid ß (Aß) plaques and may be involved in the pathogenesis and progression of Aß aggregates. Trafficking and thus maturation of these dysfunctional vacuoles is disrupted in the vicinity of Aß plaques. Transmembrane protein 55B (TMEM55B), also known as phosphatidylinositol-4,5-bisphosphate 4-phosphatase 1 (PIP4P1) is an endo-lysosomal membrane protein that is necessary for appropriate trafficking of endo-lysosomes. The present study tested whether overexpression of TMEM55B in the hippocampus could prevent plaque-associated axonal accumulation of dysfunctional endo-lysosomes, reduce Aß plaque load, and prevent hippocampal-dependent learning and memory deficits in the 5XFAD mouse models of Aß plaque pathology. Immunohistochemical analyses revealed a modest but significant reduction in the accumulation of endo-lysosomes in dystrophic neurites surrounding Aß plaques, but there was no change in hippocampal-dependent memory or plaque load. Overall, these data indicate a potential role for TMEM55B in reducing endo-lysosomal dysfunction during AD-like Aß pathology.

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease.

Glycosylation is the most common form of post-translational modification in the brain. Aberrant glycosylation has been observed in cerebrospinal fluid and brain tissue of Alzheimer's disease (AD) cases, including dysregulation of terminal sialic acid (SA) modifications. While alterations in sialylation have been identified in AD, the localization of SA modifications on cellular or aggregate-associated glycans is largely unknown because of limited spatial resolution of commonly utilized methods. The present study aims to overcome these limitations with novel combinations of histologic techniques to characterize the sialylation landscape of O- and N-linked glycans in autopsy-confirmed AD post-mortem brain tissue. Sialylated glycans facilitate important cellular functions including cell-to-cell interaction, cell migration, cell adhesion, immune regulation, and membrane excitability. Previous studies have not investigated both N- and O-linked sialylated glycans in neurodegeneration. In this study, the location and distribution of sialylated glycans were evaluated in three brain regions (frontal cortex, hippocampus, and cerebellum) from 10 AD cases using quantitative digital pathology techniques. Notably, we found significantly greater N-sialylation of the Aß plaque microenvironment compared with O-sialylation. Plaque-associated microglia displayed the most intense N-sialylation proximal to plaque pathology. Further analyses revealed distinct differences in the levels of N- and O-sialylation between cored and diffuse Aß plaque morphologies. Interestingly, phosphorylated tau pathology led to a slight increase in N-sialylation and no influence of O-sialylation in these AD brains. Confirming our previous observations in mice with novel histologic approach, these findings support microglia sialylation appears to have a relationship with AD protein aggregates while providing potential targets for therapeutic strategies.

Increased α-2,6 sialic acid on microglia in amyloid pathology is resistant to oseltamivir.

Terminal sialic acid residues are present on most glycoproteins and glycolipids, but levels of sialylation are known to change in the brain throughout the lifespan as well as during disease. Sialic acids are important for numerous cellular processes including cell adhesion, neurodevelopment, and immune regulation as well as pathogen invasion into host cells. Neuraminidase enzymes, also known as sialidases, are responsible for removal of terminal sialic acids in a process known as desialylation. Neuraminidase 1 (Neu1) cleaves the α-2,6 bond of terminal sialic acids. Aging individuals with dementia are often treated with the antiviral medication oseltamivir, which is associated with induction of adverse neuropsychiatric side effects; this drug inhibits both viral and mammalian Neu1. The present study tested whether a clinically relevant antiviral dosing regimen of oseltamivir would disrupt behavior in the 5XFAD mouse model of Alzheimer's disease amyloid pathology or wild-type littermates. While oseltamivir treatment did not impact mouse behavior or modify amyloid plaque size or morphology, a novel spatial distribution of α-2,6 sialic acid residues was discovered in 5XFAD mice that was not present in wild-type littermates. Further analyses revealed that α-2,6 sialic acid residues were not localized the amyloid plaques but instead localized to plaque-associated microglia. Notably, treatment with oseltamivir did not alter α-2,6 sialic acid distribution on plaque-associated microglia in 5XFAD mice which may be due to downregulation of Neu1 transcript levels in 5XFAD mice. Overall, this study suggests that plaque-associated microglia are highly sialylated and are resistant to change with oseltamivir, thus interfering with microglia immune recognition of and response to amyloid pathology.

L-type calcium channel antagonist isradipine age-dependently decreases plaque associated dystrophic neurites in 5XFAD mouse model.

Epidemiological studies suggest that L-type calcium channel (LTCC) antagonists may reduce the incidence of age-associated neurodegenerative diseases including Alzheimer's disease (AD). However, the neuroprotective mechanism of LTCC antagonists is unknown. Amyloid-ß (Aß) pathology disrupts intracellular calcium signaling, which regulates lysosomes and microglial responses. Neurons near Aß plaques develop dystrophic neurites, which are abnormal swellings that accumulate lysosomes. Further, microglia accumulate around Aß plaques and secrete inflammatory cytokines. We hypothesized that antagonism of LTCCs with isradipine would reduce Aß plaque-associated dystrophic neurites and inflammatory microglia in the 5XFAD mouse model by restoring normal intracellular calcium regulation. To test this hypothesis, we treated 6- and 9-month-old 5XFAD mice with isradipine and tested behavior, examined Aß plaques, microglia, and dystrophic neurites. We found that isradipine treatment age-dependently reduces dystrophic neurites and leads to trending decreases in Aß but does not modulate plaque associated microglia regardless of age. Our findings provide insight into how antagonizing LTCCs alters specific cell types in the Aß plaque environment, providing valuable information for potential treatment targets in future AD studies.