Rob Veerhuis

(Neuro)inflammation and neuroprogression as new pathways and drug targets in depression: from antioxidants to kinase inhibitors.

In 1993 the first review on the inflammatory findings in depression was published (Maes, 1993). The second review on this topic (Maes, 1995) appeared in this journal that now publishes a special state-of-the art issueon the inflammatorypathways indepression. The initial so-called “monocyte-T lymphocyte”, “cytokine” or “inflammatory” hypothesis was based on findings on increased levels of proinflammatory cytokines produced bymonocytic cells/macrophages, e.g. interleukin-1β (IL-1β), IL6, and tumor necrosis factor-α (TNFα); and T lymphocytes, e.g. interferon-γ (IFNγ) and IL-2, in depression, and entailed 6 statements (Maes, 1995, 1997; Maes et al., 1995):

Whether, when and how chronic inflammation increases the risk of developing late-onset Alzheimer's disease

Neuropathological studies have revealed the presence of a broad variety of inflammation-related proteins (complement factors, acute-phase proteins, pro-inflammatory cytokines) in Alzheimers disease (AD) brains. These constituents of innate immunity are involved in several crucial pathogenic events of the underlying pathological cascade in AD, and recent studies have shown that innate immunity is involved in the etiology of late-onset AD. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. Neuropathological and experimental studies indicate that fibrillar amyloid-β (Aβ) can activate the innate immunity-related CD14 and Toll-like receptor signaling pathways of glial cells for pro-inflammatory cytokine production. The production capacity of this pathway is under genetic control and offspring with a parental history of late-onset AD have a higher production capacity for pro-inflammatory cytokines. The activation of microglia by fibrillar Aβ deposits in the early preclinical stages of AD can make the brain susceptible later on for a second immune challenge leading to enhanced production of pro-inflammatory cytokines. An example of a second immune challenge could be systemic inflammation in patients with preclinical AD. Prospective epidemiological studies show that elevated serum levels of acute phase reactants can be considered as a risk factor for AD. Clinical studies suggest that peripheral inflammation increases the risk of dementia, especially in patients with preexistent cognitive impairment, and accelerates further deterioration in demented patients. The view that peripheral inflammation can increase the risk of dementia in older people provides scope for prevention.

Innate Immunity and the Etiology of Late-Onset Alzheimer's Disease

Background: Neuropathological studies supported by experimental animal studies show that the constituents of the innate immunity are intimately involved in the early steps of the pathological cascade of Alzheimer’s disease (AD). Objectives: To show the evidence that constituents of the innate immunity contribute to the etiology of late-onset AD. Methods: Evaluation of the relationship between the constituents of the innate immunity and genetic risk factors for late-onset AD. Results: Complement activation and activated microglia are early neuropathogical events in AD brains. Genome-wide association studies have demonstrated gene loci that are linked to the complement system. The production capacity for inflammatory cytokines is under genetic control and the offspring with a parental history of late-onset AD have a higher production capacity for inflammatory cytokines. Conclusion: Epidemiological and genetic data suggest that the innate immunity is involved in the etiology of late-onset AD.

Direct Downregulation of CNTNAP2 by STOX1A is Associated with Alzheimer's Disease

STOX1A is a transcription factor which is functionally and structurally similar to the forkhead box protein family. STOX1A has been shown to be associated with pre-eclampsia, a pregnancy associated disease, and to have potential implications in late onset Alzheimers disease. However, the exact function of STOX1A and its target genes are still largely unknown. Therefore, in this study we performed chromatin immunoprecipitation coupled to shotgun cloning to discover novel STOX1A target genes. Our results show that CNTNAP2, a member of the neurexin family, is directly downregulated by STOX1A. Additionally, we show that CNTNAP2 expression is downregulated in the hippocampus of Alzheimers disease patients where STOX1A expression has been shown to be upregulated. In conclusion, these results further indicate the potential involvement of STOX1A and its target genes in the etiology of Alzheimers disease.

Aminobisphosphonates inhibit dendritic cell-mediated antigen-specific activation of CD1d-restricted iNKT cells

CD1d-restricted invariant natural killer T (iNKT) cells constitute an important immunoregulatory T cell subset that can be activated by the synthetic glycolipid α-galactosylceramide (α-GalCer) and initiate antitumor immune responses. As cancer patients are frequently treated with aminobisphosphonates (NBP), it is relevant to determine possible effects of NBP on CD1d-restricted glycolipid Ag-presentation to iNKT cells. We report a striking reduction of α-GalCer-induced iNKT cell activation by monocyte derived dendritic cells (moDC) upon their exposure to NBP during maturation. We found that production of apolipoprotein E (apoE), which is a known facilitator of trans-membrane transport of exogenously derived glycolipids, was significantly diminished in moDC exposed to NBP. As the inhibitory effect of NBP on iNKT cell activation was alleviated by exogenous apoE, our data indicate that reduced apoE production by antigen presenting cells (APC) through NBP limits glycolipid-induced iNKT cell activation. This should be taken into account in the design of iNKT cell-based anti-cancer therapies.

IRAK-4 KINASE INHIBITION REDUCES PRO-INFLAMMATORY CYTOKINE SECRETION BUT HAS NO EFFECT ON THE UPTAKE OF AMYLOID BETA BY HUMAN GLIAL CELLS

which function in innate immunity also suggests that innate immunity may have a significant role in AD. Given that gliosis occurs at least decades earlier than the first appearance of clinical symptoms in AD, it is conceivable that glial dysfunction and mis-activation of the innate immune system drives AD type neurodegeneration.However, very few studies have directly addressed how inflammation per se drives Ab or tau pathology.To characterize the role of innate immunefactors on amyloid b (Ab) plaque and tau pathology, we overexpressed several mouse cytokines, chemokine receptors and soluble innate immune receptors in Amyloid precursor protein (APP) expressingTgCRND8 mice or tau transgenic mice. Methods: Using adeno associated virus (AAV2/1) mediated gene delivery in neonatal mice brain, we effectively demonstrate that this technique allows us to achieve high levels of transgene expression while 1) bypassing the need to create bigenic mice to test hypotheses in a rapid cost-effective manner, 2) testing different mediators on a uniform genetic background and 3) modeling cell non autonomous signaling in vivo. Results: We show that in TgCRND8 mice brain, expression of 1) inflammatory cytokines reduce Ab plaques; 2) anti-inflammatory cytokines exacerbate Ab pathology; and 3) modulating the innate immune receptors using soluble Toll-like receptors (sTLR4 and sTLR5) decrease Ab pathology. On the other hand, over-expression of inflammatory cytokines increase soluble phosphorylated tau while differentially affecting insoluble tau levels in tau transgenic mice. Conclusions: Understanding how innate immune activation states regulate tau and Abpathology could reveal novel therapeutic approaches for AD, including re-purposing current forms of immune therapy already tested in the clinic. Our ongoing studies show that manipulating innate immunity can be a double edged sword, and that development of any innate immune therapy for AD will need to be finely tuned and extensively validated in order to be truly effective. We demonstrate that though engagement of the innate immune system early on during disease pathogenesis may be beneficial in restricting the development of Ab plaques, this may potentially exacerbate tau pathology and negatively affect proteostasis. Therefore, our study strongly argues for a cautious re-examination of unwarranted side-effects of immune based therapies and calls for exploring the therapeutic potential of decoy receptors in preclinical mouse models ofAD as a means of restricting AD pathology while simultaneously minimizing bystander toxicity.

Beta-amyloid oligomer detection in cerebrospinal fluid and brain tissue

major health and social care challenges for the 21st century worldwide. The global number of people with dementia was calculated at 36 million by 2010 and is estimated to increase to 66 million by 2030 and 115 million by 2050 (World Alzheimer Report 2009). The global cost is estimated at US

Amyloid and Microbleeds in different dementias: retained or drained?

604 billion by 2010 (World Alzheimer Report 2010). Governments and societies are not prepared to these challenges. Therefore Alzheimer’s Disease International (ADI), the global federation of Alzheimer associations is campaigning to make dementia a global health priority with programs of World Health Organization (WHO) and United Nations (UN). Methods: ADI has started an advocacy program towards WHO and UN meetings including training of national advocates, creating an international network and visiting international and regional meetings and make statements, contact country representatives and produce data on prevalence and cost of illness. Results: Dementia was included in the Mental Health Global Action Programme of WHO as a priority area. The UN High Level Meeting on Non-Communicable Diseases in September 2011 adopted a paragraph on the importance of mental health and Alzheimer’s disease. The WHO is going to release a report Dementia: A Public Health Priority by April 2012. A resolution on ageing will be put forward at the annual WHO assembly in May 2012. Conclusions: Alzheimer’s disease and dementia have become part of the international health agenda. This needs to be implemented in national and subnational action plans. This has happened in a few countries like Australia, Korea, France and England. A plan for the USA is on its way. Monitoring and evaluation of those plans will be crucial as well as securing the funding. Countries without a plan need to be encouraged to develop.

Alzheimer’s disease and adult neurogenesis—Are endogenous stem cells part of the solution?

Background:Microbleeds (MBs) in dementia have been associated with cerebral amyloid angiopathy in Alzheimer disease (AD) and vascular dementia (VaD). MBs may be related to amyloid changes, measurable in CSF, and impacted by blood-brain barrier (BBB) function impairment.We studied the relation between MBs and amyloid beta in CSF and plasma, combined with BBB function in patients with dementia, compared to subjective complainers. Methods: From our memoryclinic, we included 26 probable AD patients with MBs and age/sex-matched 26 AD patients without MBs, and additionally 12 VaD patients and 22 patients with subjective complaints. MBs were assessed using 3T MRI. Amyloid beta 1-40 (Aß40), amyloid beta 1-42 (Aß42) and albuminweremeasured in CSF and plasma. BBB function was estimated using CSF/serum albumin ratios. Results: CSFA ß42 levels differed between groups and were lowest in AD patients with MBs, (429[pg/ml] 6 119 [SD], p < 0.05) followed by AD patients without MBs (550 6 212, p < 0.05) and VaD (429 6 119) and finally patients with subjective complaints (8516 244, p< 0.05). CSFAß40was lower in VaD (8686 6 2785) than all other groups (p < 0.05), but did not differ between AD patients with (11043 6 3478) or without MBs (11569 6 3517) and subjective complaints (12024 6 2882, p < 0.05). In plasma, Aß42 and Aß40 were elevated inVaD patients (p< 0.05) compared to the other groups. Only inVaD, the albumin ratio was increased (p < 0.05), suggesting BBB dysfunction. Conclusions: Low CSF Aß levels are differentially implicated in AD with MBs and VaD. Whereas Aß42 is low in CSF and seems retained in the brain parenchyma and vessels in AD, especially in cases with MBs, BBB dysfunction seems to allow drainage of Aß40 and Aß42 from the brain in VaD, resulting in low CSF and high Aß plasma levels in VaD.

CSF ApoE predicts clinical progression in nondemented APOEε4 carriers

The human brain produces new neurons that mediate hippocampal plasticity but also have a potential role in hippocampal-related disorders, such as Alzheimer’s disease and dementia. Factors such as stress and aging that reduce adult neurogenesis also serve as independent risk factors for Alzheimer’s disease. Causality between loss of neurogenesis and hippocampal dysfunction has not been established; however, neurogenesis is an attractive research avenue for therapy since it is readily modifiable. Activities such as running and enrichment increase the proliferation of neural stem cells and survival of nascent neuroblasts. Adult neurogenesis may alternatively reflect capacity to overcome age-dependent insults and neurodegeneration in the hippocampus. This collectively indicates that stimulation of endogenous cells or transplantation of neural stem cells are potential pathways reversing the behavioral changes associated with neurodegenerative disorders by augmenting structural plasticity of the hippocampus. Continued research in this area and in appropriate animal models of disease is critical for evaluating whether neurogenesis-based therapeutic strategies will have the potential to aid those with degenerative conditions.