R. Veerhuis

Bio: R. Veerhuis is an academic researcher from VU University Medical Center. The author has contributed to research in topics: Neuroinflammation & Microglia. The author has an hindex of 18, co-authored 28 publications receiving 5807 citations.

The unfolded protein response is activated in Alzheimer's disease.

Abstract: Alzheimer's disease (AD) is, at the neuropathological level, characterized by the accumulation and aggregation of misfolded proteins. The presence of misfolded proteins in the endoplasmic reticulum (ER) triggers a cellular stress response called the unfolded protein response (UPR) that may protect the cell against the toxic buildup of misfolded proteins. In this study we investigated the activation of the UPR in AD. Protein levels of BiP/GRP78, a molecular chaperone which is up-regulated during the UPR, was found to be increased in AD temporal cortex and hippocampus as determined by Western blot analysis. At the immunohistochemical level intensified staining of BiP/GRP78 was observed in AD, which did not co-localize with AT8-positive neurofibrillary tangles. In addition, we performed immunohistochemistry for phosphorylated (activated) pancreatic ER kinase (p-PERK), an ER kinase which is activated during the UPR. p-PERK was observed in neurons in AD patients, but not in non-demented control cases and did not co-localize with AT8-positive tangles. Overall, these data show that the UPR is activated in AD, and the increased occurrence of BiP/GRP78 and p-PERK in cytologically normal-appearing neurons suggest a role for the UPR early in AD neurodegeneration. Although the initial participation of the UPR in AD pathogenesis might be neuroprotective, sustained activation of the UPR in AD might initiate or mediate neurodegeneration.

Neuroinflammation – An Early Event in Both the History and Pathogenesis of Alzheimer’s Disease

Abstract: Background: About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. Objectives: To show that the interest in inflammation in Alzheimer’s disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. Methods: Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. Results: Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. Conclusion: Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau-related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD.

Decreased lysophosphatidylcholine/phosphatidylcholine ratio in cerebrospinal fluid in Alzheimer's disease.

Abstract: Choline containing phospholipids are essential for the integrity of the'cell'membrane. Minor changes in the lysophosphatidylcholine (lyso-PC)/phosphatidylcholine (PC) ratio may lead to neuronal damage and cell loss. Several studies have shown protein and lipid oxidation in Alzheimer’s disease (AD) affected brain regions. Amyloid-β peptides may induce free-radical oxidative stress which normally is counteracted by anti-oxidant defense mechanisms. We hypothesize that oxidation may lead to changed concentrations of choline containing phospholipids in cerebrospinal fluid (CSF) of AD patients, because of the susceptibility of the unsaturated acyl-chains of PC for oxidation. PC and lyso-PC were determined in CSF of AD patients (n=19) and subjects with subjective memory complaints without dementia (n=19) by tandem mass spectrometry. No differences in total PC concentrations were observed between both study groups. Furthermore, we could not demonstrate different concentrations of PC species containing linoleic acid and PC species containing arachidonic acid. Interestingly, lyso-PC concentrations tended to be lower while the lyso-PC/PC ratio was significantly decreased in CSF of AD patients compared to controls (0.36% versus 0.54%; P=0.017). A comparable decrease was found for the lyso-PC/PC ratio for PC containing linoleic acid (P=0.022) or arachidonic acid (P=0.010), respectively. The lower lyso-PC/PC ratio in CSF of patients with AD may reflect alterations in the metabolism of choline-containing phospholipids in the brain in AD, and suggests that PC species containing linoleic acid or arachidonic acid are equally involved.

Structural and functional features of central nervous system lymphatic vessels

Abstract: One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system. Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood. In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.

Intraneuronal beta-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation.

Abstract: Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ42 production. 5XFAD mice generate Aβ42 almost exclusively and rapidly accumulate massive cerebral Aβ42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Aβ42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloid plaque formation.

Variant of TREM2 associated with the risk of Alzheimer's disease

Abstract: Background: Sequence variants, including the e4 allele of apolipoprotein E, have been associated with the risk of the common late-onset form of Alzheimer's disease. Few rare variants affecting the risk of late-onset Alzheimer's disease have been found. Methods: We obtained the genome sequences of 2261 Icelanders and identified sequence variants that were likely to affect protein function. We imputed these variants into the genomes of patients with Alzheimer's disease and control participants and then tested for an association with Alzheimer's disease. We performed replication tests using case-control series from the United States, Norway, the Netherlands, and Germany. We also tested for a genetic association with cognitive function in a population of unaffected elderly persons. Results: A rare missense mutation (rs75932628-T) in the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2), which was predicted to result in an R47H substitution, was found to confer a significant risk of Alzheimer's disease in Iceland (odds ratio, 2.92; 95% confidence interval [CI], 2.09 to 4.09; P = 3.42×10-10). The mutation had a frequency of 0.46% in controls 85 years of age or older. We observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P = 2.1×10-12 in combined discovery and replication samples). We also found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P = 0.003). Conclusions: Our findings strongly implicate variant TREM2 in the pathogenesis of Alzheimer's disease. Given the reported antiinflammatory role of TREM2 in the brain, the R47H substitution may lead to an increased predisposition to Alzheimer's disease through impaired containment of inflammatory processes. (Funded by the National Institute on Aging and others.) Copyright