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Background Triggering receptor expressed on myeloid cell-2 (TREM2) is a lipid and lipoprotein binding receptor expressed by cells of myeloid origin. Homozygous TREM2 mutations cause early onset progressive presenile dementia while heterozygous, point mutations triple the risk of Alzheimer’s disease (AD). Although human genetic findings support the notion that loss of TREM2 function exacerbates neurodegeneration, it is not clear whether activation of TREM2 in a disease state would result in therapeutic benefits. To determine the viability of TREM2 activation as a therapeutic strategy, we sought to characterize an agonistic Trem2 antibody (AL002a) and test its efficacy and mechanism of action in an aggressive mouse model of amyloid deposition. Methods To determine whether agonism of Trem2 results in therapeutic benefits, we designed both intracranial and systemic administration studies. 5XFAD mice in the intracranial administration study were assigned to one of two injection groups: AL002a, a Trem2-agonizing antibody, or MOPC, an isotype-matched control antibody. Mice were then subject to a single bilateral intracranial injection into the frontal cortex and hippocampus and euthanized 72 h later. The tissue from the left hemisphere was histologically examined for amyloid-beta and microglia activation, whereas the tissue from the right hemisphere was used for biochemical analyses. Similarly, mice in the systemic administration study were randomized to one of the aforementioned injection groups and the assigned antibody was administered intraperitoneally once a week for 14 weeks. Mice underwent behavioral assessment between the 12- and 14-week timepoints and were euthanized 24 h after their final injection. The tissue from the left hemisphere was used for histological analyses whereas the tissue from the right hemisphere was used for biochemical analyses. Results Here, we show that chronic activation of Trem2, in the 5XFAD mouse model of amyloid deposition, leads to reversal of the amyloid-associated gene expression signature, recruitment of microglia to plaques, decreased amyloid deposition, and improvement in spatial learning and novel object recognition memory. Conclusions These findings indicate that Trem2 activators may be effective for the treatment of AD and possibly other neurodegenerative disorders.

Vascular dementia (VaD) is the second leading cause of dementia behind Alzheimer's disease (AD) and is a frequent comorbidity with AD, estimated to occur in as many as 40% of AD patients. The causes of VaD are varied and include chronic cerebral hypoperfusion, microhemorrhages, hemorrhagic infarcts, or ischemic infarcts. We have developed a model of VaD by inducing hyperhomocysteinemia (HHcy) in wild-type mice. By placing wild-type mice on a diet deficient in folate, B6, and B12 and supplemented with excess methionine, we induced a moderate HHcy (plasma level homocysteine 82.93 ± 3.561 μmol). After 11 weeks on the diet, the hyperhomocysteinemic mice showed a spatial memory deficit as assessed by the 2-day radial-arm water maze. Also, magnetic resonance imaging and subsequent histology revealed significant microhemorrhage occurrence. We found neuroinflammation induced in the hyperhomocysteinemic mice as determined by elevated interleukin (IL)-1β, tumor necrosis factor (TNF)α, and IL-6 in brain tissue. Finally, we found increased expression and increased activity of the matrix metalloproteinase 2 (MMP2) and MMP9 systems that are heavily implicated in the pathogenesis of cerebral hemorrhage. Overall, we have developed a dietary model of VaD that will be valuable for studying the pathophysiology of VaD and also for studying the comorbidity of VaD with other dementias and other neurodegenerative disorders.

Over recent years, the retina has been increasingly investigated as a potential biomarker for dementia. A number of studies have looked at the effect of Alzheimer’s disease (AD) pathology on the retina and the associations of AD with visual deficits. However, while OCT-A has been explored as a biomarker of cerebral small vessel disease (cSVD), studies identifying the specific retinal changes and mechanisms associated with cSVD are lacking. Using our model of hyperhomocysteinemia-induced cSVD, we aimed to identify the effects of cSVD on visual sensitivity and cognition, retinal glial and vascular cells, and neuroinflammatory and cardiovascular gene expression changes. We placed C57Bl6/SJL mice on a HHcy-inducing diet, a model that has been well characterized to have vascular pathologies in the brain similar to pathologic cSVD. After 14 weeks on diet, mice underwent the Visual-Stimuli 4-arm Maze to identify visual deficits. Whole mount retinas were stained for vessels, microglia and astrocytes to identify glial and vascular changes. Finally, neuroinflammatory and cardiovascular gene expression was measured using NanoString’s nCounter system. Ultimately, HHcy led to visual changes that specifically affected the reaction to blue and white light, slightly decreased vascular volume and significantly decreased interaction of microglia with the vasculature, as well as downregulation of inflammatory and vascular genes. These changes provide novel insights and reproduce some prior observations. These studies highlight retinal changes in association with cSVD and serve as a precaution when interpreting vision-dependent cognitive testing of cSVD models.

Background Epidemiological data suggests statins could reduce the risk of dementia, and more specifically, Alzheimer’s disease (AD). Pre-clinical data suggests statins reduce the risk of dementia through their pleiotropic effects rather than their cholesterol lowering effects. While AD is a leading cause of dementia, it is frequently found co-morbidly with cerebral small vessel disease and other vascular contributions to cognitive impairment and dementia (VCID), which are another leading cause of dementia. In this study, we determined if atorvastatin ameliorated hyperhomocysteinemia (HHcy)-induced VCID. Methods Wild-type (C57Bl6/J) mice were placed on a diet to induce HHcy or a control diet each with or without atorvastatin for 14 weeks. Mice underwent novel object recognition testing before tissue collection. Plasma total cholesterol and total homocysteine as well as related metabolites were measured. Using qPCR and NanoString technology, we profiled glial cell-associated gene expression changes. Finally, microglial morphology, astrocyte end feet, and microhemorrhages were analyzed using histological methods. Results Atorvastatin treatment of HHcy in mice led to no changes in total cholesterol but decreases in total homocysteine in plasma. While HHcy decreased expression of many glial genes, atorvastatin rescued these gene changes, which mostly occurred in oligodendrocytes and microglia. Microglia in HHcy mice with atorvastatin were trending towards fewer processes compared to control with atorvastatin, but there were no atorvastatin effects on astrocyte end feet. While atorvastatin treatment was trending towards increasing the area of microhemorrhages in HHcy mice in the frontal cortex, it only slightly (non-significantly) reduced the number of microhemorrhages. Finally, atorvastatin treatment in HHcy mice led to improved cognition on the novel object recognition task. Conclusions These data suggest that atorvastatin rescued cognitive changes induced by HHcy most likely through lowering plasma total homocysteine and rescuing gene expression changes rather than impacts on vascular integrity or microglial changes.

Background Vascular contributions to cognitive impairment and dementia (VCID) are the second leading cause of dementia behind only Alzheimer’s disease (AD); however, VCID is commonly found as a co-morbidity with sporadic AD. We have previously established a mouse model of VCID by inducing hyperhomocysteinemia in both wild-type and amyloid depositing mice. While we have shown the time course of neuropathological events in the wild-type mice with hyperhomocysteinemia, the effect of amyloid deposition on this time course remains unknown; therefore, in this study, we determined the time course of neuropathological changes in our mouse model of hyperhomocysteinemia-induced VCID in amyloid depositing mice. Methods APP/PS1 mice were placed on either a diet deficient in folate and vitamins B6 and B12 and enriched in methionine to induce hyperhomocysteinemia or a control diet for 2, 6, 10, 14, or 18 weeks. Immunohistochemistry and gene expression analysis were used to determine neuroinflammatory changes. Microhemorrhages and amyloid deposition were analyzed using histology and, finally, behavior was assessed using the 2-day radial arm water maze. Results Neuroinflammation, specifically a pro-inflammatory phenotype, was the first pathological change to occur. Specifically, we see a significant increase in gene expression of tumor necrosis factor alpha, interleukin 1 beta, interleukin 6, and interleukin 12a by 6 weeks. This was followed by cognitive deficits starting at 10 weeks. Finally, there is a significant increase in the number of microhemorrhages at 14 weeks on diet as well as redistribution of amyloid from the parenchyma to the vasculature. Conclusions The time course of these pathologies points to neuroinflammation as the initial, key player in homocysteine-induced VCID co-morbid with amyloid deposition and provides a possible therapeutic target and time points.

Introduction We evaluated the relationship between plasma levels of transactive response DNA binding protein of 43 kDa (TDP‐43) and neuroimaging (magnetic resonance imaging [MRI]) measures of brain structure in aging. Methods Plasma samples were collected from 72 non‐demented older adults (age range 60–94 years) in the University of Kentucky Alzheimer's Disease Research Center cohort. Multivariate linear regression models were run with plasma TDP‐43 level as the predictor variable and brain structure (volumetric or cortical thickness) measurements as the dependent variable. Covariates included age, sex, intracranial volume, and plasma markers of Alzheimer's disease neuropathological change (ADNC). Results Negative associations were observed between plasma TDP‐43 level and both the volume of the entorhinal cortex, and cortical thickness in the cingulate/parahippocampal gyrus, after controlling for ADNC plasma markers. Discussion Plasma TDP‐43 levels may be directly associated with structural MRI measures. Plasma TDP‐43 assays may prove useful in clinical trial stratification. HIGHLIGHTS Plasma transactive response DNA binding protein of 43 kDa (TDP‐43) levels were associated with entorhinal cortex volume. Biomarkers of TDP‐43 and Alzheimer's disease neuropathologic change (ADNC) may help distinguish limbic‐predominant age‐related TDP‐43 encephalopathy neuropathologic change (LATE‐NC) from ADNC. A comprehensive biomarker kit could aid enrollment in LATE‐NC clinical trials.

High plasma levels of homocysteine, termed hyperhomocysteinemia, are a risk factor for vascular cognitive impairment and dementia, which is the second leading cause of dementia. While hyperhomocysteinemia induces microhemorrhages and cognitive decline in mice, the specific effect of hyperhomocysteinemia on each cell type remains unknown. We took separate cultures of astrocytes, microglia, endothelial cells, and neuronal cells and treated each with moderate levels of homocysteine for 24, 48, 72, and 96 hr. We then determined the gene expression changes for cell-specific markers and neuroinflammatory markers including the matrix metalloproteinase 9 system. Astrocytes had decreased levels of several astrocytic end feet genes, such as aquaporin 4 and an adenosine triphosphate (ATP)-sensitive inward rectifier potassium channel at 72 hr, as well as an increase in matrix metalloproteinase 9 at 48 hr. Gene changes in microglia indicated a peak in proinflammatory markers at 48 hr followed by a peak in the anti-inflammatory marker, interleukin 1 receptor antagonist, at 72 hr. Endothelial cells had reduced occludin expression at 72 hr, while kinases and phosphatases known to alter tau phosphorylation states were increased in neuronal cells. This suggests that hyperhomocysteinemia induces early proinflammatory changes in microglia and astrocytic changes relevant to their interaction with the vasculature. Overall, the data show how hyperhomocysteinemia could impact Alzheimer’s disease and vascular cognitive impairment and dementia.

Agglomerative hierarchical clustering analysis (HCA) is a commonly used unsupervised machine learning approach for identifying informative natural clusters of observations. HCA is performed by calculating a pairwise dissimilarity matrix and then clustering similar observations until all observations are grouped within a cluster. Verifying the empirical clusters produced by HCA is complex and not well studied in biomedical applications. Here, we demonstrate the comparability of a novel HCA technique with one that was used in previous biomedical applications while applying both techniques to plasma angiogenic (FGF, FLT, PIGF, Tie-2, VEGF, VEGF-D) and inflammatory (MMP1, MMP3, MMP9, IL8, TNFα) protein data to identify informative subsets of individuals. Study subjects were diagnosed with mild cognitive impairment due to cerebrovascular disease (MCI-CVD). Through comparison of the two HCA techniques, we were able to identify subsets of individuals, based on differences in VEGF ( < 0.001), MMP1 ( < 0.001), and IL8 ( < 0.001) levels. These profiles provide novel insights into angiogenic and inflammatory pathologies that may contribute to VCID.

Lithium is an anti-psychotic that has been shown to prevent the hyperphosphorylation of tau protein through the inhibition of glycogen-synthase kinase 3-beta (GSK3β). We recently developed a mouse model that progresses from amyloid pathology to tau pathology and neurodegeneration due to the genetic deletion of NOS2 in an APP transgenic mouse; the APPSwDI/NOS2-/- mouse. Because this mouse develops tau pathology, amyloid pathology and neuronal loss we were interested in the effect anti-tau therapy would have on amyloid pathology, learning and memory. We administered lithium in the diets of APPSwDI/NOS2-/- mice for a period of eight months, followed by water maze testing at 12 months of age, immediately prior to sacrifice. We found that lithium significantly lowered hyperphosphorylated tau levels as measured by Western blot and immunocytochemistry. However, we found no apparent neuroprotection, no effect on spatial memory deficits and an increase in histological amyloid deposition. Aβ levels measured biochemically were unaltered. We also found that lithium significantly altered the neuroinflammatory phenotype of the brain, resulting in enhanced alternative inflammatory response while concurrently lowering the classical inflammatory response. Our data suggest that lithium may be beneficial for the treatment of tauopathies but may not be beneficial for the treatment of Alzheimer's disease.

Background The polarization to different neuroinflammatory phenotypes has been described in early Alzheimer’s disease, yet the impact of these phenotypes on amyloid-beta (Aβ) pathology remains unknown. Short-term studies show that induction of an M1 neuroinflammatory phenotype reduces Aβ, but long-term studies have not been performed that track the neuroinflammatory phenotype. Methods Wild-type and APP/PS1 transgenic mice aged 3 to 4 months received a bilateral intracranial injection of adeno-associated viral (AAV) vectors expressing IFNγ or green fluorescent protein in the frontal cortex and hippocampus. Mice were sacrificed 4 or 6 months post-injection. ELISA measurements were used for IFNγ protein levels and biochemical levels of Aβ. The neuroinflammatory phenotype was determined through quantitative PCR. Microglia, astrocytes, and Aβ levels were assessed with immunohistochemistry. Results AAV expressing IFNγ induced an M1 neuroinflammatory phenotype at 4 months and a mixed phenotype along with an increase in Aβ at 6 months. Microglial staining was increased at 6 months and astrocyte staining was decreased at 4 and 6 months in mice receiving AAV expressing IFNγ. Conclusions Expression of IFNγ through AAV successfully induced an M1 phenotype at 4 months that transitioned to a mixed phenotype by 6 months. This transition also appeared with an increase in amyloid burden suggesting that a mixed phenotype, or enhanced expression of M2a and M2c markers, could contribute to increasing amyloid burden and disease progression.