Amyloid Clearance Research Articles

Blood-Brain Barrier ABC-transporter P-glycoprotein in Alzheimer's Disease: Still a Suspect?

Alzheimer's disease is a neurodegenerative disorder and the most common form of dementia. One of the pathological hallmarks of the disease is amyloid deposition in the brain. The major cause of amyloid deposition in sporadic Alzheimer's disease is thought to be decreased brain clearance of amyloid. There is compelling preclinical evidence that the blood-brain barrier, a structure that maintains homeostasis in the central nervous system and protects the brain from harmful substances, plays an important role in amyloid clearance. Indeed, several dedicated transporter systems are present at the blood-brain barrier which may have a role in brain amyloid clearance, such as P-glycoprotein (P-gp). In vitro experiments and animal studies indicated increased amyloid deposition when P-gp was eliminated by pharmacological blockade or by genetic modification. And as decreased P-gp expression has been found in AD brains, P-gp became more and more a suspect. Using an imaging technique called positron emission tomography, P-gp transporter function was found to be decreased in Alzheimer's disease patients compared to healthy controls, further establishing the important role of P-gp in the pathogenesis of the disease. In this review, we summarize what is now known about P-gp in Alzheimer's disease pathology, as these transporters may provide a novel target for therapeutic strategies.

Prophylactic Vaccine Based on Pyroglutamate-3 Amyloid β Generates Strong Antibody Response and Rescues Cognitive Decline in Alzheimer’s Disease Model Mice

Clearance of amyloid β (Aβ) by immunotherapy is one of the fancy methods to treat Alzheimer's disease (AD). However, the failure of some clinical trials suggested that there may be something ignored in the past development of immunotherapy. Pyroglutamate-3 Aβ (AβpE3-X), which was found to be abundant in the patients' brain, has attracted much attention after the report that AβpE3-42 could serve as a template to exacerbate the aggregation of Aβ. In addition, AβpE3-X could not be recognized by the antibodies targeting the N-terminus of Aβ, suggesting that AβpE3-X maybe the ignored one. Indeed, passive immunization targeting AβpE3-X has shown some beneficial results, while active immunotherapy has not been extensively studied. In the present study, we designed and synthesized a novel peptide vaccine targeting AβpE3-X, which contains AβpE3-15 as B cell epitope and P2 as T cell epitope. We showed that this vaccine could induce strong antibody response to AβpE3-X. We also showed that prophylactic immunization of AD model mice with our vaccine could reduce Aβ plaques and rescue cognitive decline. This new kind of Aβ vaccine will open up new directions for AD immunotherapy.

Fructus Corni Officinalis water extract Ameliorates Memory Impairment and Beta amyloid (Aβ) clearance by LRP-1 Expression in the Hippocampus of a Rat model of Alzheimer’s Disease

This study evaluated the effects of Fructus Corni Officinalis water extract (FCE) on congnitive impairment and Aβ clearance induced by beta amyloid Aβ (1-42) injection in the hippocampus of rat. Aβ (1-42) was injected into the hippocampus using a Hamilton syringe and micropump (5 ㎍/5 ㎕, 1 ㎕/min, each hippocampus bilaterally). FCE was administered orally once a day (100, 250, 500 ㎎/㎏) for 4 weeks after the Aβ (1-42) injection. The acquisition of learning and retention of memory were tested using the Morris water maze. Aβ accumulation and Aβ clearance in the hippocampus were observed using immunostaining. Aβ (1-42) level in plasma was confirmed using enzyme-linked immunosorbent assay (ELISA). FCE significantly shortened the escape latencies during acquisition training trials. FCE significantly increased the number of target heading to the platform site and significantly shortened the time for the 1 st targetheadingduringtheretentiontesttrial.FCEsignificantlyattenuatedtheAβ accumulation in the hippocampus produced by Aβ (1-42) injection. FCE significantly increased LRP-1 expression around vessels in the hippocampus and Aβ (1-42) levels in plasma. The results suggest that FCE improved cognitive impairment by ameliorate Aβ clearance and Aβ accumulation in the hippocampus. FCE may be a beneficial herbal formulation in treating cognitive impairment including Alzheimer’s disease.

Deposition, Clearance, and Reinduction of Amyloid A Amyloid in Interleukin 1 Receptor Antagonist Knockout Mice.

Amyloid A (AA) amyloidosis is characterized by the extracellular deposition of AA amyloid and results in the irreversible dysfunction of parenchymal organs. In experimental models, AA amyloid deposits are cleared following a decrease in circulating serum amyloid A (SAA) concentrations. Additional inflammatory stimuli during this recovery process may induce more severe amyloid redeposition. In the present study, we confirmed the deposition, clearance, and reinduction of AA amyloid deposits in interleukin 1 receptor antagonist knockout mice (IL-1raKO) and studied the SAA levels and amyloid-enhancing factor activity based on the time-dependent changes of amyloid deposition. Histopathologically, following initial (day 0) injection of amyloid-enhancing factor in combination with an inflammatory stimulus (silver nitrate [AgNO3]), amyloid deposition peaked by day 20, and its deposition gradually decreased after day 35. SAA concentrations in serum were precipitously elevated on day 1 but returned to normal levels by day 10, whereas the SAA dimer was detected in serum after day 45. An additional AgNO3 injection was administered to mice with amyloidosis on day 5, 10, 35, or 50, and all mice developed large amyloid deposits. Amyloid deposition was most severe in mice treated with AgNO3 on day 35. The inoculation of sera from mice with AA amyloidosis, combined with AgNO3, induced AA amyloidosis. Serum samples collected on days 35 and 50, which contained high concentrations of the SAA dimer, induced amyloidosis in a high proportion (83%) of mice. Therefore, increased SAA and/or its dimer in serum during the recovery process may markedly exacerbate the development of AA amyloidosis.

Reduced Efficacy of Anti-Aβ Immunotherapy in a Mouse Model of Amyloid Deposition and Vascular Cognitive Impairment Comorbidity.

Vascular cognitive impairment and dementia (VCID) is the second most common form of dementia behind Alzheimer's disease (AD). It is estimated that 40% of AD patients also have some form of VCID. One promising therapeutic for AD is anti-Aβ immunotherapy, which uses antibodies against Aβ to clear it from the brain. While successful in clearing Aβ and improving cognition in mice, anti-Aβ immunotherapy failed to reach primary cognitive outcomes in several different clinical trials. We hypothesized that one potential reason the anti-Aβ immunotherapy clinical trials were unsuccessful was due to this high percentage of VCID comorbidity in the AD population. We used our unique model of VCID-amyloid comorbidity to test this hypothesis. We placed 9-month-old wild-type and APP/PS1 mice on either a control diet or a diet that induces hyperhomocysteinemia (HHcy). After being placed on the diet for 3 months, the mice then received intraperotineal injections of either IgG2a control or 3D6 for another 3 months. While we found that treatment of our comorbidity model with 3D6 resulted in decreased total Aβ levels, there was no cognitive benefit of the anti-Aβ immunotherapy in our AD/VCID mice. Further, microhemorrhages were increased by 3D6 in the APP/PS1/control but further increased in an additive fashion when 3D6 was administered to the APP/PS1/HHcy mice. This suggests that the use of anti-Aβ immunotherapy in patients with both AD and VCID would be ineffective on cognitive outcomes. Despite significant mouse model data demonstrating both pathological and cognitive efficacy of anti-Aβ immunotherapy for the treatment of Alzheimer's disease, clinical trial outcomes have been underwhelming, failing to meet any primary endpoints. We show here that vascular cognitive impairment and dementia (VCID) comorbidity eliminates cognitive efficacy of anti-Aβ immunotherapy, despite amyloid clearance. Further, cerebrovascular adverse events of the anti-Aβ immunotherapy are significantly exacerbated by the VCID comorbidity. These data suggest that VCID comorbidity with Alzheimer's disease may mute the response to anti-Aβ immunotherapy.

Cerebral amyloid is associated with greater white-matter hyperintensity accrual in cognitively normal older adults

Cross-sectional studies show that elevated cerebral amyloid is associated with greater white-matter hyperintensity (WMH) burden in cognitively normal (CN) older adults. However, the relative time courses of amyloid and WMH accrual are unclear. To address this, we tested the associations between known WMH correlates—age, hypertension, and amyloid—with WMH accrual rate. We used brain magnetic resonance imaging to measure WMH change in 112 CN Alzheimer's Disease Neuroimaging Initiative (GO/2) participants over a 2-year period. A linear mixed effects model assessed baseline cerebrospinal fluid amyloid beta (Aβ) 1–42, hypertension, age, and their interactions, as predictors of greater WMH accrual. Greater amyloid burden was associated with greater WMH accrual over time. Those with hypertension showed a stronger association between greater amyloid burden and WMH accrual rate. Greater age was not significantly associated with greater WMH accrual in this model. Although the direction of the relationship cannot be tested in this model, CN individuals harboring cerebral amyloid had greater accrual of WMH over a 2-year period after accounting for hypertension and age. Impaired amyloid clearance and cerebral small vessel disease may both underlie the more rapid emergence of WM lesions. The role of cerebral amyloid burden in white-matter injury should thus be considered as a relevant factor when WMHs are detected clinically.

Cerebral Arterial Occlusion Did Not Promote the Prevalence of Cerebral Amyloid Angiopathy.

An impairment of amyloid-β (Aβ) clearance has been suggested in Alzheimer's disease. Perivascular drainage along cerebrovascular vessels is considered an important amyloid clearance pathway. This study examined the effect of reduced arterial pulsation that could cause an impairment in cerebral amyloid drainage on the prevalence of cortical microbleeds (CMBs), a surrogate marker for cerebral amyloid angiopathy (CAA). Patients who lost depiction of either side of the carotid artery or the middle cerebral artery on magnetic resonance angiography were studied. Those who showed acute cerebral infarction or a previous cortical cerebral infarction were excluded. The number of CMBs was counted on the occluded and non-occluded sides of the brain in each subject. The number of subjects who showed more CMBs on the occluded side of the brain was compared with the number of subjects who showed more CMBs on the non-occluded side of the brain. Twenty-eight patients were studied. The extent of lacunar infarction and white matter lesions was not different, irrespective of the occluded vessels or the distribution of CMBs. The prevalence of CMBs was not different between the occluded and non-occluded sides of the brain. In this cross-sectional study, reduction of arterial pulsation was not associated with a higher prevalence of CAA. Therefore, reduced arterial pulsation alone may not be enough to promote CAA.

Systemic amyloidosis: novel therapies and role of biomarkers.

Systemic amyloidosis is caused by misfolding and extracellular deposition of one of an ever-growing list of circulating proteins, resulting in vital organ dysfunction and eventually death. Despite different predisposing conditions, including plasma cell dyscrasias [immunoglobulin light chain (AL) amyloidosis], long-lasting inflammation [reactive (AA) amyloidosis] or mutations (hereditary amyloidoses), clinical manifestations are conspicuously overlapping and mimic more prevalent conditions, significantly complicating and often delaying the recognition of these rare, complex diseases. However, refined diagnostic and imaging approaches and the increasing role of biomarkers, which help in establishing the diagnosis, assessing the prognosis and evaluating the response to therapy, have considerably improved the management of these conditions. The pillar of anti-amyloid therapy remains the prompt reduction or elimination of the amyloidogenic precursor. This is accomplished by targeting the underlying condition, and recent improvements in the treatment of plasma cell disorders and chronic inflammatory conditions have positively reverberated onto the management of AL and AA amyloidosis, respectively. Moreover, recent, substantial improvements in the understanding of the molecular underpinnings of systemic amyloidosis have unveiled different key steps in the amyloidogenic cascade which can be valid therapeutic targets. These include stabilizers of the native conformation of the amyloidogenic precursor, inhibitors of fibrillogenesis, amyloid fibril disruptors and promoters of amyloid clearance. Innovative pharmacological strategies, including rational, structure-based drug design, gene knockdown and immunotherapy, but also repurposing of old, safe drugs with newly recognized anti-amyloid properties, are currently being pursued already in the clinical setting, holding the promise of dramatically improving the outcome of these dismal conditions in the near future.

TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance.

Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β‐peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor‐mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody‐mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD. Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti‐Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose‐dependent manner in the presence or absence of TREM2. However, TREM2‐deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody‐bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.

2A4 binds soluble and insoluble light chain aggregates from AL amyloidosis patients and promotes clearance of amyloid deposits by phagocytosis

Amyloid light chain (AL) amyloidosis is characterized by misfolded light chain (LC) (amyloid) deposition in various peripheral organs, leading to progressive dysfunction and death. There are no regulatory agency–approved treatments for AL amyloidosis, and none of the available standard of care approaches directly targets the LC protein that constitutes the amyloid. NEOD001, currently in late-stage clinical trials, is a conformation-specific, anti-LC antibody designed to specifically target misfolded LC aggregates and promote phagocytic clearance of AL amyloid deposits. The present study demonstrated that the monoclonal antibody 2A4, the murine form of NEOD001, binds to patient-derived soluble and insoluble LC aggregates and induces phagocytic clearance of AL amyloid in vitro. 2A4 specifically labeled all 21 fresh-frozen organ samples studied, which were derived from 10 patients representing both κ and λ LC amyloidosis subtypes. 2A4 immunoreactivity largely overlapped with thioflavin T–positive labeling, and 2A4 bound both soluble and insoluble LC aggregates extracted from patient tissue. Finally, 2A4 induced macrophage engagement and phagocytic clearance of AL amyloid deposits in vitro. These findings provide further evidence that 2A4/NEOD001 can effectively clear and remove human AL-amyloid from tissue and further support the rationale for the evaluation of NEOD001 in patients with AL amyloidosis.

TREM2 CLEARANCE OF AMYLOID: PERIPHERAL VS. CNS-DERIVED CELLS

TREM2 CLEARANCE OF AMYLOID: PERIPHERAL VS. CNS-DERIVED CELLS

How immune cells clear amyloid

How immune cells clear amyloid

Alzheimer's Disease Risk Genes and Lipid Regulators.

Brain lipid homeostasis plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Aggregation of amyloid-β peptide is one of the major events in AD. The complex interplay between lipids and amyloid-β accumulation has been intensively investigated. The proportions of lipid components including phospholipids, sphingolipids, and cholesterol are roughly similar across different brain regions under physiological conditions. However, disruption of brain lipid homeostasis has been described in AD and implicated in disease pathogenesis. Moreover, studies suggest that analysis of lipid composition in plasma and cerebrospinal fluid could improve our understanding of the disease development and progression, which could potentially serve as disease biomarkers and prognostic indicators for AD therapies. Here, we summarize the functional roles of AD risk genes and lipid regulators that modulate brain lipid homeostasis including different lipid species, lipid complexes, and lipid transporters, particularly their effects on amyloid processing, clearance, and aggregation, as well as neuro-toxicities that contribute to AD pathogenesis.

Over-Expressed Pathogenic miRNAs in Alzheimer's Disease (AD) and Prion Disease (PrD) Drive Deficits in TREM2-Mediated Aβ42 Peptide Clearance.

One prominent and distinguishing feature of progressive, age-related neurological diseases such as Alzheimer’s disease (AD) and prion disease (PrD) is the gradual accumulation of amyloids into dense, insoluble end-stage protein aggregates. These polymorphic proteolipid lesions are known to contribute to immunogenic and inflammatory pathology in these insidious and fatal disorders of the human central nervous system (CNS). For example, the evolution of self-aggregating amyloid-beta (Aβ) peptides, such as the 42 amino acid Aβ42 peptide monomer into higher order aggregates are largely due to: (1) the inability of natural processes to clear them from the cellular environment; and/or (2) the overproduction of these amyloid monomers which rapidly mature into higher order oligomers, fibrils and insoluble, end-stage senile plaques. Cells of the CNS such as microglial (MG) cells have evolved essential homeostatic mechanisms to clear Aβ peptides to avoid their accumulation, however, when defective, these clearance mechanisms become overwhelmed and excessive deposition and aggregation of these amyloids result. This ‘Perspectives’ paper will highlight some emerging concepts on the up-regulation of an inducible microRNA-34a in AD and PrD that drives the down-regulation of the amyloid sensing- and clearance receptor protein TREM2 (the triggering receptor expressed in myeloid/microglial cells). The impairment of this inducible, miRNA-34a-regulated TREM2- and MG-cell based amyloid clearance mechanism may thereby contribute to the age-related amyloidogenesis associated with both AD and PrD.

A Role for P-Glycoprotein in Clearance of Alzheimer Amyloid β -Peptide from the Brain.

Most data indicates that Alzheimer's disease involves an accumulation of amyloid β - peptide (Aβ) in the CNS and that sporadic cases arise from a deficiency in Aβ clearance. Considerable attention has been given to mechanisms by which Aβ might be transported between the brain and blood, and evidence suggests that p-glycoprotein, also known as the multi-drug resistance (MDR) protein (product of the ABCB1 gene), plays a role in Aβ transport across the blood-brain barrier (BBB). We tested this possibility through two approaches: First, wild-type and MDR1A-knockout mice were compared after intravenous injection of [(125)I]-labeled Aβ; after 60 min, homogenates of brain parenchyma were subjected to γ-counting of TCA-precipitable material, and histological sections of brain were subjected to autoradiography. Second, MDR1Aknockout mice were crossed with Tg2576 APP transgenic mice, a line that routinely accumulates Aβ in the brain; SDS and formic acid extracts of brain homogenates were assessed for Aβ levels by ELISA. Each of these approaches yielded data indicating that Aβ accumulates to a greater degree in mice lacking MDR1A. These findings confirm other reports linking p-glycoprotein to Aβ clearance across the BBB and have important implications for Alzheimer's disease genetics, pharmacology, and epidemiology.

Examining the immunomodulatory effects of IL‐12 in a mouse model of Alzheimer's Disease

Interleukin‐12 (IL‐12) is known to be a differentiation factor for naïve T‐cells into Th1 cells. We have previously used IL‐12 as a systemic therapeutic agent to clear Amyloid Beta (Aβ) peptides in a transgenic APPswe/PS1dE9 mouse model for Alzheimer's Disease. It was found that a modest decrease in Aβ plaque formation in this model using IL‐12 was associated with increased microglial activation using the marker, Ionized calcium‐binding adaptor molecule 1 (Iba1), also known as Allograft inflammatory factor 1 (AIF‐1). Iba1 is known to be expressed on activated microglial cells during an inflammatory response in the brain. In this study, we examined whether additional consecutive doses of IL‐12 would further magnify microglial activation in the brain. At 18 months old, wild type or AD mice were injected subcutaneously with IL‐12 once a week (20 ng) and sacrificed at day 21 or 42 (3 weeks vs 6 weeks). Mice were divided into the following groups: 1) WT mice, 2) WT mice with IL‐12 (3 weeks), 3) WT mice with IL‐12 (6 weeks) 4) AD mice, 5) AD mice with IL‐12 (3 weeks), and 6) AD mice with IL‐12 (6 weeks). Mouse brains were perfused and brain slices were quantitated by immunohistochemical (IHC) methods using imaging software for Aβ 1–40 or Aβ 1–42 peptides in AD brains, and for Iba1 in all groups. We further quantitated IL‐12rβ2 (IL‐12 receptor) using similar IHC techniques, in order to examine whether systemic IL‐12 administration also resulted in upregulated IL‐12 receptors in the brain. The results indicate a complex neuromodulatory effect.Support or Funding InformationUCLA Department of Pathology and Laboratory Medicine

Study of Exosomes Shed New Light on Physiology of Amyloidogenesis.

Accumulation of toxic amyloid oligomers, a key feature in the pathogenesis of amyloid-related diseases, results from an imbalance between generation and clearance of amyloidogenic proteins. Cell biology has brought to light the key roles of multivesicular endosomes (MVEs) and their intraluminal vesicles (ILVs), which can be secreted as exosomes, in amyloid generation and clearance. To better understand these roles, we have investigated a relevant physiological model of amyloid formation in pigment cells. These cells have tuned their endosomes to optimize the formation of functional amyloid fibrils from the premelanosome protein (PMEL) and to avoid potential accumulation of toxic species. The functional amyloids derived from PMEL reveal striking analogies with the generation of Aβ peptides. We have recently strengthened these analogies using extracellular vesicles as reporters of the endosomal processes that regulate PMEL melanogenesis. We have shown that in pigmented cells, apolipoprotein E (ApoE) is associated with ILVs and exosomes, and regulates the formation of PMEL amyloid fibrils in endosomes. This process secures the generation of amyloid fibrils by exploiting ILVs as amyloid-nucleating platforms. This physiological model of amyloidogenesis could shed new light on the roles of MVEs and exosomes in conditions with pathological amyloid metabolism, such as Alzheimer's disease.

Novel conformation-specific monoclonal antibodies against amyloidogenic forms of transthyretin

Introduction: Transthyretin amyloidosis (ATTR amyloidosis) is caused by the misfolding and deposition of the transthyretin (TTR) protein and results in progressive multi-organ dysfunction. TTR epitopes exposed by dissociation and misfolding are targets for immunotherapeutic antibodies. We developed and characterized antibodies that selectively bound to misfolded, non-native conformations of TTR.Methods: Antibody clones were generated by immunizing mice with an antigenic peptide comprising a cryptotope within the TTR sequence and screened for specific binding to non-native TTR conformations, suppression of in vitro TTR fibrillogenesis, promotion of antibody-dependent phagocytic uptake of mis-folded TTR and specific immunolabeling of ATTR amyloidosis patient-derived tissue.Results: Four identified monoclonal antibodies were characterized. These antibodies selectively bound the target epitope on monomeric and non-native misfolded forms of TTR and strongly suppressed TTR fibril formation in vitro. These antibodies bound fluorescently tagged aggregated TTR, targeting it for phagocytic uptake by macrophage THP-1 cells, and amyloid-positive TTR deposits in heart tissue from patients with ATTR amyloidosis, but did not bind to other types of amyloid deposits or normal tissue.Conclusions: Conformation-specific anti-TTR antibodies selectively bind amyloidogenic but not native TTR. These novel antibodies may be therapeutically useful in preventing deposition and promoting clearance of TTR amyloid and in diagnosing TTR amyloidosis.

Bacopaside I ameliorates cognitive impairment in APP/PS1 mice via immune-mediated clearance of β-amyloid.

Standardized extracts of Bacopa monniera (BME) have been shown to exert a neuroprotective effect against mental diseases, such as depression, anxiety and Alzheimer's disease (AD), in chronic administration studies. However, its mechanism of action has remained unclear. In this study, we evaluated the therapeutic effect of Bacopaside I (BS-I), a major triterpenoid saponin of BME, on the cognitive impairment and neuropathology in APP/PS1 transgenic mice and explored the possible mechanism from a biological systems perspective. We found that BS-I treatment significantly ameliorated learning deficits, improved long-term spatial memory, and reduced plaque load in APP/PS1 mice. We constructed BS-I's therapeutic effect network by mapping the nodes onto the protein-protein interaction (PPI) network constructed according to their functional categories based on genomic and proteomic data. Because many of the top enrichment categories related to the processes of the immune system and phagocytosis were detected, we proposed that BS-I promotes amyloid clearance via the induction of a suitable degree of innate immune stimulation and phagocytosis. Our research may help to clarify the neuroprotective effect of BME and indicated that natural saponins target the immune system, which may offer new research avenues to discover novel treatments for AD.

Increased cerebrospinal fluid soluble TREM2 concentration in Alzheimer's disease.

BackgroundThe discovery that heterozygous missense mutations in the gene encoding triggering receptor expressed on myeloid cells 2 (TREM2) are risk factors for Alzheimer’s disease (AD), with only the apolipoprotein E (APOE) ε4 gene allele conferring a higher risk, has led to increased interest in immune biology in the brain. TREM2 is expressed on microglia, the resident immune cells of the brain and has been linked to phagocytotic clearance of amyloid β (Aβ) plaques. Soluble TREM2 (sTREM2) has previously been measured in cerebrospinal fluid (CSF) by ELISA but in our hands commercial kits have proved unreliable, suggesting that other methods may be required. We developed a mass spectrometry method using selected reaction monitoring for the presence of a TREM2 peptide, which can be used to quantify levels of sTREM2 in CSF.FindingsWe examined CSF samples from memory clinics in Sweden and the UK. For all samples the following were available: clinical diagnosis, age, sex, and measurements of the CSF AD biomarkers Aβ42, T-tau and P-tau181. AD patients (n = 37) all met biomarker (IWG2) criteria for AD. Control individuals (n = 22) were cognitively normal without evidence for AD in CSF. We found significantly higher sTREM2 concentration in AD compared to control CSF. There were significant correlations between CSF sTREM2 and T-tau as well as P-tau181. CSF sTREM2 increase in AD was replicated in a second, independent cohort consisting of 24 AD patients and 16 healthy volunteers.ConclusionCSF concentrations of sTREM2 are higher in AD than in controls, and correlate with markers of neurodegeneration. CSF sTREM2 may be used to quantify glial activation in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0071-x) contains supplementary material, which is available to authorized users.