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Alzheimer’s Disease: Novel Therapeutical Approaches — Articles of Note @PharmaceuticalIntelligence.com

Curators: Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

UPDATED on 7/23/2022

Blots on a field?

A neuroscience image sleuth finds signs of fabrication in scores of Alzheimer’s articles, threatening a reigning theory of the disease

sticky brain deposits of the protein amyloid beta (Aβ) is the prevailing theory explaining advancement of AD.

SOURCE

21 JUL 2022

BY CHARLES PILLER

https://www.science.org/content/article/potential-fabrication-research-images-threatens-key-theory-alzheimers-disease

 

The Rogue Immune Cells That Wreck the Brain

Beth Stevens thinks she has solved a mystery behind brain disorders such as Alzheimer’s and schizophrenia.

by Adam Piore   April 4, 2016            

https://www.technologyreview.com/s/601137/the-rogue-immune-cells-that-wreck-the-brain/

Microglia are part of a larger class of cells—known collectively as glia—that carry out an array of functions in the brain, guiding its development and serving as its immune system by gobbling up diseased or damaged cells and carting away debris. Along with her frequent collaborator and mentor, Stanford biologist Ben Barres, and a growing cadre of other scientists, Stevens, 45, is showing that these long-overlooked cells are more than mere support workers for the neurons they surround. Her work has raised a provocative suggestion: that brain disorders could somehow be triggered by our own bodily defenses gone bad.

In one groundbreaking paper, in January, Stevens and researchers at the Broad Institute of MIT and Harvard showed that aberrant microglia might play a role in schizophrenia—causing or at least contributing to the massive cell loss that can leave people with devastating cognitive defects. Crucially, the researchers pointed to a chemical pathway that might be targeted to slow or stop the disease. Last week, Stevens and other researchers published a similar finding for Alzheimer’s.

This might be just the beginning. Stevens is also exploring the connection between these tiny structures and other neurological diseases—work that earned her a $625,000 MacArthur Foundation “genius” grant last September.

All of this raises intriguing questions. Is it possible that many common brain disorders, despite their wide-ranging symptoms, are caused or at least worsened by the same culprit, a component of the immune system? If so, could many of these disorders be treated in a similar way—by stopping these rogue cells?

VIEW VIDEO

Science  31 Mar 2016;        http://dx.doi.org:/10.1126/science.aad8373      Complement and microglia mediate early synapse loss in Alzheimer mouse models.
Soyon Hong¹, Victoria F. Beja-Glasser¹,*, Bianca M. Nfonoyim¹,*,…., Ben A. Barres⁶, Cynthia A. Lemere,², Dennis J. Selkoe²,⁷, Beth Stevens¹,⁸,^†

Synapse loss in Alzheimer’s disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 or the microglial complement receptor CR3, reduces the number of phagocytic microglia as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.

Genome-wide association studies (GWAS) implicate microglia and complement-related pathways in AD (1). Previous research has demonstrated both beneficial and detrimental roles of complement and microglia in plaque-related neuropathology (2, 3); however, their roles in synapse loss, a major pathological correlate of cognitive decline in AD (4), remain to be identified. Emerging research implicates microglia and immune-related mechanisms in brain wiring in the healthy brain (1). During development, C1q and C3 localize to synapses and mediate synapse elimination by phagocytic microglia (5–7). We hypothesized that this normal developmental synaptic pruning pathway is activated early in the AD brain and mediates synapse loss.

Scientists have known about glia for some time. In the 1800s, the pathologist Rudolf Virchow noted the presence of small round cells packing the spaces between neurons and named them “nervenkitt” or “neuroglia,” which can be translated as nerve putty or glue. One variety of these cells, known as astrocytes, was defined in 1893. And then in the 1920s, the Spanish scientist Pio del Río Hortega developed novel ways of staining cells taken from the brain. This led him to identify and name two more types of glial cells, including microglia, which are far smaller than the others and are characterized by their spidery shape and multiple branches. It is only when the brain is damaged in adulthood, he suggested, that microglia spring to life—rushing to the injury, where it was thought they helped clean up the area by eating damaged and dead cells. Astrocytes often appeared on the scene as well; it was thought that they created scar tissue.

This emergency convergence of microglia and astrocytes was dubbed “gliosis,” and by the time Ben Barres entered medical school in the late 1970s, it was well established as a hallmark of neurodegenerative diseases, infection, and a wide array of other medical conditions. But no one seemed to understand why it occurred. That intrigued Barres, then a neurologist in training, who saw it every time he looked under a microscope at neural tissue in distress. “It was just really fascinating,” he says. “The great mystery was: what is the point of this gliosis? Is it good? Is it bad? Is it driving the disease process, or is it trying to repair the injured brain?”

Barres began looking for the answer. He learned how to grow glial cells in a dish and apply a new recording technique to them. He could measure their electrical qualities, which determine the biochemical signaling that all brain cells use to communicate and coördinate activity.

Barres’s group had begun to identify the specific compounds astrocytes secreted that seemed to cause neurons to grow synapses. And eventually, they noticed that these compounds also stimulated production of a protein called C1q.

Conventional wisdom held that C1q was activated only in sick cells—the protein marked them to be eaten up by immune cells—and only outside the brain. But Barres had found it in the brain. And it was in healthy neurons that were arguably at their most robust stage: in early development. What was the C1q protein doing there?

https://d267cvn3rvuq91.cloudfront.net/i/images/glia33.jpg?sw=590&cx=0&cy=0&cw=2106&ch=2106

A stained astrocyte.

The answer lies in the fact that marking cells for elimination is not something that happens only in diseased brains; it is also essential for development. As brains develop, their neurons form far more synaptic connections than they will eventually need. Only the ones that are used are allowed to remain. This pruning allows for the most efficient flow of neural transmissions in the brain, removing noise that might muddy the signal.

Kalaria, RN. Microglia and Alzheimer’s disease. Current Opinion in Hematology: January 1999 – Volume 6 – Issue 1 – p 15

Microglia play a major role in the cellular response associated with the pathological lesions of Alzheimer’s disease. As brain-resident macrophages, microglia elaborate and operate under several guises that seem reminiscent of circulating and tissue monocytes of the leucocyte repertoire. Although microglia bear the capacity to synthesize amyloid β, current evidence is most consistent with their phagocytic role. This largely involves the removal of cerebral amyloid and possibly the transformation of amyloid β into fibrils. The phagocytic functions also encompass the generation of cytokines, reactive oxygen and nitrogen species, and various proteolytic enzymes, events that may exacerbate neuronal damage rather than incite outgrowth or repair mechanisms. Microglia do not appear to function as true antigen-presenting cells. However, there is circumstantial evidence that suggests functional heterogeneity within microglia. Pharmacological agents that suppress microglial activation or reduce microglial-mediated oxidative damage may prove useful strategies to slow the progression of Alzheimer’s disease.

Streit WJ. Microglia and Alzheimer’s disease pathogenesis. J Neurosci Res 1 July 2004; 77(1):1–8
http://dx.doi.org:/10.1002/jnr.20093

The most visible and, until very recently, the only hypothesis regarding the involvement of microglial cells in Alzheimer’s disease (AD) pathogenesis is centered around the notion that activated microglia are neurotoxin-producing immune effector cells actively involved in causing the neurodegeneration that is the cause for AD dementia. The concept of detrimental neuroinflammation has gained a strong foothold in the AD arena and is being expanded to other neurodegenerative diseases. This review takes a comprehensive and critical look at the overall evidence supporting the neuroinflammation hypothesis and points out some weaknesses. The current work also reviews evidence for an alternative theory, the microglial dysfunction hypothesis, which, although eliminating some of the shortcomings, does not necessarily negate the amyloid/neuroinflammation theory. The microglial dysfunction theory offers a different perspective on the identity of activated microglia and their role in AD pathogenesis taking into account the most recent insights gained from studying basic microglial biology.

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Kira Irving Mosher^a, b, Tony Wyss-Coray^a, c. Microglial dysfunction in brain aging and Alzheimer’s disease.

Review – Part of the Special Issue: Alzheimer’s Disease – Amyloid, Tau and Beyond. Biochemical Pharmacology 15 Apr 2014; 88(4):594–604   doi:10.1016/j.bcp.2014.01.008

Microglia, the immune cells of the central nervous system, have long been a subject of study in the Alzheimer’s disease (AD) field due to their dramatic responses to the pathophysiology of the disease. With several large-scale genetic studies in the past year implicating microglial molecules in AD, the potential significance of these cells has become more prominent than ever before. As a disease that is tightly linked to aging, it is perhaps not entirely surprising that microglia of the AD brain share some phenotypes with aging microglia. Yet the relative impacts of both conditions on microglia are less frequently considered in concert. Furthermore, microglial “activation” and “neuroinflammation” are commonly analyzed in studies of neurodegeneration but are somewhat ill-defined concepts that in fact encompass multiple cellular processes. In this review, we have enumerated six distinct functions of microglia and discuss the specific effects of both aging and AD. By calling attention to the commonalities of these two states, we hope to inspire new approaches for dissecting microglial mechanisms.

http://ars.els-cdn.com/content/image/1-s2.0-S000629521400032X-fx1.jpg

 

A Olmos-Alonso, STT Schetters, S Sri, K Askew, …, VH Perry, D Gomez-Nicola.
Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer’s-like pathology. Brain 8 Jan 2016.  http://dx.doi.org/10.1093/brain/awv379

The proliferation and activation of microglial cells is a hallmark of several neurodegenerative conditions. This mechanism is regulated by the activation of the colony-stimulating factor 1 receptor (CSF1R), thus providing a target that may prevent the progression of conditions such as Alzheimer’s disease. However, the study of microglial proliferation in Alzheimer’s disease and validation of the efficacy of CSF1R-inhibiting strategies have not yet been reported. In this study we found increased proliferation of microglial cells in human Alzheimer’s disease, in line with an increased upregulation of the CSF1R-dependent pro-mitogenic cascade, correlating with disease severity. Using a transgenic model of Alzheimer’s-like pathology (APPswe, PSEN1dE9; APP/PS1 mice) we define a CSF1R-dependent progressive increase in microglial proliferation, in the proximity of amyloid-β plaques. Prolonged inhibition of CSF1R in APP/PS1 mice by an orally available tyrosine kinase inhibitor (GW2580) resulted in the blockade of microglial proliferation and the shifting of the microglial inflammatory profile to an anti-inflammatory phenotype. Pharmacological targeting of CSF1R in APP/PS1 mice resulted in an improved performance in memory and behavioural tasks and a prevention of synaptic degeneration, although these changes were not correlated with a change in the number of amyloid-β plaques. Our results provide the first proof of the efficacy of CSF1R inhibition in models of Alzheimer’s disease, and validate the application of a therapeutic strategy aimed at modifying CSF1R activation as a promising approach to tackle microglial activation and the progression of Alzheimer’s disease.

The neuropathology of Alzheimer’s disease shows a robust innate immune response characterized by the presence of activated microglia, with increased or de novo expression of diverse macrophage antigens (Akiyama et al., 2000; Edison et al., 2008), and production of inflammatory cytokines (Dickson et al., 1993; Fernandez-Botran et al., 2011). Evidence indicates that non-steroidal anti-inflammatory drugs (NSAIDs) protect from the onset or progression of Alzheimer’s disease (Hoozemans et al., 2011), suggestive of the idea that inflammation is a causal component of the disease rather than simply a consequence of the neurodegeneration. In fact, inflammation (Holmes et al., 2009), together with tangle pathology (Nelson et al., 2012) or neurodegeneration-related biomarkers (Wirth et al., 2013) correlate better with cognitive decline than amyloid-b accumulation, but the underlying mechanisms of the sequence of events that contribute to the clinical symptoms are poorly understood. The contribution of inflammation to disease pathogenesis is supported by recent genome-wide association studies, highlighting immune-related genes such as CR1 (Jun et al., 2010), TREM2 (Guerreiro et al., 2013; Jonsson et al., 2013) or HLA-DRB5–HLA-DRB1 in association with Alzheimer’s disease (European Alzheimer’s Disease et al., 2013). Additionally, a growing body of evidence suggests that systemic inflammation may interact with the innate immune response in the brain to act as a ‘driver’ of disease progression and exacerbate symptoms (Holmes et al., 2009, 2011). Microglial cells are the master regulators of the neuroin- flammatory response associated with brain disease (GomezNicola and Perry, 2014a, b). Activated microglia have been demonstrated in transgenic models of Alzheimer’s disease (LaFerla and Oddo, 2005; Jucker, 2010) and have been recently shown to dominate the gene expression landscape of patients with Alzheimer’s disease (Zhang et al., 2013). Recently, microglial activation through the transcription factor PU.1 has been reported to be capital for the progression of Alzheimer’s disease, highlighting the role of microglia in the disease-initiating steps (Gjoneska et al., 2015). Results from our group, using a murine model of chronic neurodegeneration (prion disease), show large numbers of microglia with an activated phenotype (Perry et al., 2010) and a cytokine profile similar to that of Alzheimer’s disease (Cunningham et al., 2003). The expansion of the microglial population during neurodegeneration is almost exclusively dependent upon proliferation of resident cells (GomezNicola et al., 2013, 2014a; Li et al., 2013). An increased microglial proliferative activity has also been described in a mouse model of Alzheimer’s disease (Kamphuis et al., 2012) and in post-mortem samples from patients with Alzheimer’s disease (Gomez-Nicola et al., 2013, 2014b). This proliferative activity is regulated by the activation of the colony stimulating factor 1 receptor (CSF1R; GomezNicola et al., 2013). Pharmacological strategies inhibiting the kinase activity of CSF1R provide beneficial effects on the progression of chronic neurodegeneration, highlighting the detrimental contribution of microglial proliferation (Gomez-Nicola et al., 2013). The presence of a microglial proliferative response with neurodegeneration is also supported by microarray analysis correlating clinical scores of incipient Alzheimer’s disease with the expression of Cebpa and Spi1 (PU.1), key transcription factors controlling microglial lineage commitment and proliferation (Blalock et al., 2004). Consistent with these data, Csf1r is upregulated in mouse models of amyloidosis (Murphy et al., 2000), as well as in human post-mortem samples from patients with Alzheimer’s disease (Akiyama et al., 1994). Although these ideas would lead to the evaluation of the efficacy of CSF1R inhibitors in Alzheimer’s disease, we have little evidence regarding the level of microglial proliferation in Alzheimer’s disease or the effects of CSF1R targeting in animal models of Alzheimer’s disease-like pathology. In this study, we set out to define the microglial proliferative response in both human Alzheimer’s disease and a mouse model of Alzheimer’s disease-like pathology, as well as the activation of the CSF1R pathway. We provide evidence for a consistent and robust activation of a microglial proliferative response, associated with the activation of CSF1R. We provide proof-of-target engagement and efficacy of an orally available CSF1R inhibitor (GW2580), which inhibits microglial proliferation and partially prevents the pathological progression of Alzheimer’s disease-like pathology, supporting the evaluation of CSF1R-targeting approaches as a therapy for Alzheimer’s disease.

Post-mortem samples of Alzheimer’s disease For immunohistochemical analysis, human brain autopsy tissue samples (temporal cortex, paraffin-embedded, formalin- fixed, 96% formic acid-treated, 6-mm sections) from the National CJD Surveillance Unit Brain Bank (Edinburgh, UK) were obtained from cases of Alzheimer’s disease (five females and five males, age 58–76) or age-matched controls (four females and five males, age 58–79), in whom consent for use of autopsy tissues for research had been obtained. All cases ful- filled the criteria for the pathological diagnosis of Alzheimer’s disease. Ethical permission for research on autopsy materials stored in the National CJD Surveillance Unit was obtained from Lothian Region Ethics Committee

Figure 1 Characterization of the microglial proliferative response in Alzheimer’s disease. (A–C) Immunohistochemical analysis and quantification of the number of total microglial cells (Iba1+ ; A) or proliferating microglial cells (Iba1+Ki67 + ; B) in the grey (GM) and white matter (WM) of the temporal cortex of Alzheimer’s disease cases (AD) and age-matched non-demented controls (NDC). (C) Representative pictures of the localization of a marker of proliferation (Ki67, dark blue) in microglial cells (Iba1+ , brown) in the grey matter of the temporal cortex of non-demented controls or Alzheimer’s disease cases. (D) RT-PCR analysis of the mRNA expression of CSF1R, CSF1, IL34, SPI1 (PU.1), CEBPA, RUNX1 and PCNA in the temporal cortex of Alzheimer’s disease cases and age-matched non-demented controls. Expression of mRNA represented as mean SEM and indicated as relative expression to the normalization factor (geometric mean of four housekeeping genes; GAPDH, HPRT, 18S and GUSB) using the 2-CT method. Statistical differences: *P 50.05, **P 50.01, ***P 50.001. Data were analysed with a two-way ANOVA and a post hoc Tukey test (A and B) or with a two-tailed Fisher t-test (D). Scale bar in C = 50 mm.

Increased microglial proliferation and CSF1R activity are closely associated with the progression of Alzheimer’s disease-like pathology 

Pharmacological targeting of CSF1R activation with an orally-available inhibitor blocks microglial proliferation in APP/PS1 mice

CSF1R inhibition prevents the progression of Alzheimer’s disease-like pathology

The innate immune component has a clear influence over the onset and progression of Alzheimer’s disease. The analysis of therapeutic approaches aimed at controlling neuroinflammation in Alzheimer’s disease is moving forward at the preclinical and clinical level, with several clinical trials aimed at modulating inflammatory components of the disease. We have previously demonstrated that the proliferation of microglial cells is a core component of the neuroinflammatory response in a model of prion disease, another chronic neurodegenerative disease, and is controlled by the activation of CSF1R (Gomez-Nicola et al., 2013). This aligns with recent reports pinpointing the causative effect of the activation of the microglial proliferative response on the neurodegenerative events of human and mouse Alzheimer’s disease, highlighting the activity of the master regulator PU.1 (Gjoneska et al., 2015). Our results provide a proof of efficacy of CSF1R inhibition for the blockade of microglial proliferation in a model of Alzheimer’s disease-like pathology. Treatment with the orally available CSF1R kinase-inhibitor (GW2580) proves to be an effective disease-modifying approach, partially improving memory and behavioural performance, and preventing synaptic degeneration. These results support the previously reported link of the inflammatory response generated by microglia in models of Alzheimer’s disease with the observed synaptic and behavioural deficits, regardless of amyloid deposition (Jones and Lynch, 2014).

Our findings support the relevance of CSF1R signalling and microglial proliferation in chronic neurodegeneration and validate the evaluation of CSF1R inhibitors in clinical trials for Alzheimer’s disease. Our findings show that the inhibition of microglial proliferation in a model of Alzheimer’s disease-like pathology does not modify the burden of amyloid-b plaques, suggesting an uncoupling of the amyloidogenic process from the pathological progression of the disease.

 

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Keywords:

• Alzheimer’s disease

• microglia
• gliosis
• neurodegeneration
• inflammation