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Cerebrospinal fluid concentrations of p-tau/Aβ42 associate with cognitive decline in Alzheimer’s disease, mild cognitive impairment, and cognitively unimpaired older adultsMcKenna, Michael Robert January 2021 (has links)
No description available.
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GPR50, a potential factor involved in psychiatric disorders interacts with Alzheimer's disease-related protein β-secretase (BACE1)Li, Qian January 2014 (has links)
GPR50, an X-linked orphan G protein-coupled receptor (GPCR), is a risk factor for bipolar disorder (BD) in female subjects. It has been shown that GPR50 plays a part in neurite outgrowth, glucocorticoid receptor signalling and leptin signalling by interacting with major factors involved in these events. Yeast two-hybrid screens have identified multiple putative GPR50 interactors involved in neurodevelopment, stress response and apoptosis, lipid and glucose metabolism, as well as regulation of NMDA receptors and GABA transmission. Among these interactors, RTN3, RTN4, SREBP2 and SNX6 are known regulators of β-secretase (BACE1), a key enzyme in Aβ generation, myelination of the central/peripheral nerve, and neurite outgrowth/synapse formation. Preliminary data indicated that GPR50 expression significantly increased endogenous BACE1 activity in HEK293 cells, so I hypothesised that there is a functional interaction between the two. In this thesis, I investigated the relationship between GPR50 and BACE1 by identifying the effects of GPR50 on BACE1 expression and function, which may provide an explanation of GPR50’s potential association with psychiatric disorders and Alzheimer’s disease. Firstly, studies on expression levels revealed that when GPR50 was over-expressed, BACE1 protein expression was up-regulated in SH-SY5Y cells, but down-regulated in HEK293 cells, suggesting a differentiated regulative system between cell lines. Then I confirmed the physical association between endogenous GPR50 and BACE1 in HEK293 cells by co-localisation and co-immunoprecipitation studies. Their putative interaction sites were located at the plasma membrane and the filopodia/lamellipodia-like structures in HEK293 cells, and at the neurites in mouse primary neuronal cells. Subcellular fractionation of adult mouse brain revealed that endogenous Gpr50 and Bace1 were co-fractionated in the presynaptic vesicles. Secondly, I showed that, in contrast to HEK293 cells, GPR50 overexpression had no effects on β-secretase activity in mouse primary cortical neurons. However, the BD-associated variant GPR50del significantly decreased β-secretase activity compared to the more common variant GPR50, and showed a trend of diminishing β-secretase activity compared to the control condition. Subcellular fractionation experiments showed that in HEK293 cells, there was an increased ratio of mature BACE1 against immature BACE1 localised in the plasma membrane fractions, indicating a role in regulation of BACE1 trafficking to one of its putative activity sites; whereas in mouse primary cortical neurons, GPR50del increased co-fractionation of immature Bace1 with endoplasmic reticulum (ER) marker calreticulin, thus potentially retarding the maturation of Bace1. Importantly, the regulative trend of GPR50/GPR50del on β-secretase activity is cell line-specific and is highly correlated to their effects on β-secretase intracellular distribution. Thirdly, I found that the mRNA levels of human GPR50 and BACE1 were negatively correlated in the dorsolateral prefrontal cortex of female subjects sampled after birth. Mouse Gpr50 and Bace1 mRNA levels were negatively correlated across the telencephalon regions, and had a trend of negative correlation across the hypothalamic regions. Co-localisation of the two proteins was detected in multiple mouse brain regions, with the strongest co-localised signals occurring in CA2 pyramidal neurons, arcuate hypothalamic nucleus and dorsomedial nucleus of the hypothalamus. Finally, preliminary experiments in Alzheimer’s disease model TgSwDI mice, suggested that the expression level of Gpr50 in layer V of the entorhinal cortex was positively correlated with Aβ deposition. Decreased Gpr50 expression was identified in the hippocampus of 9 months transgenic animals compared with age-matched controls. This indicates that Gpr50 expression might be altered in this mouse model co-ordinately with Aβ deposition. The findings in this thesis provide further evidence of GPR50’s correlation to psychiatric illnesses and its interaction with enzyme BACE1 highlights a potential link to neurodegenerative disease.
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Effects of creatine supplementation on muscle metabolism in an Alzheimer mouse modelFarshidfar, Farnaz 15 February 2016 (has links)
Alzheimer’s disease (AD), the most common form of dementia in the elderly, is a global issue affecting about 24 million individuals. Because AD is a systemic pathology, dementia is not the only leading factor contributing to loss of independence in AD patients. AD may also impair skeletal muscle metabolism and function. Creatine (CR) supplementation may enhance skeletal muscle hypertrophy/mass and function in sarcopenia and muscular dystrophies, but has yet to be studied in AD. This study examined the effect of oral CR on muscle metabolism in a triple-transgenic (3xTg) AD mouse model. Twenty-four, 3×Tg AD mice (~8 month-old) were randomly assigned to control (CON) or CR (3% w/w) diet. Bodyweights and feed intakes were measured throughout the 8-week study. Lower limb (quadriceps muscle; QM and gastrocnemius; GM) and upper limb muscles (triceps; TM) were collected to analyze levels of CR, total protein, DNA, RNA, amino acids (AA), adenosine triphosphate (ATP), adenosine diphosphate (ADP), total and phosphorylated p70 ribosomal S6 kinase (p70S6K). Data (mean ± SEM) were assessed by analysis of variance (ANOVA) and Fisher’s least significant difference (LSD) post hoc test. In comparison to the CON group, CR supplementation increased CR content in both GM (p=0.002) and QM (p=0.037), with higher (p=0.032) ATP/ADP ratio in CR in comparison with CON in QM. A higher protein concentration (p<0.0001) was notable in GM of CR supplemented group vs. CON. Total branched-chain AA levels in QM increased 2-fold (p< 0.0001) in CR groups. Additionally, CR resulted in a higher (p<0.05) protein/DNA ratio; an index of muscle cell size, in both QM and GM for CR groups. The index of cell capacity for protein synthesis (RNA/DNA ratio) in GM was also higher (p=0.001) in CR groups. However, phosphorylation (activation) level of p70S6K, an integral component in protein synthesis signalling pathway, did not show any significant differences in female (p=0.161) and male (p=0.292) CR supplemented groups compared with CON. To conclude, CR supplementation is capable of inducing muscle hypertrophy/growth parameters in the 3×Tg AD mouse model, thereby enhancing protein synthesis capacity in skeletal muscles, thus possibly promoting muscle function in AD. / May 2016
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Amyloid-β and chronic cerebral hypoperfusion in the early pathogenesis of Alzheimer's diseaseSalvadores Bersezio, Natalia January 2016 (has links)
Alzheimer’s disease (AD) is a severe age-related neurodegenerative disorder and is the most common form of dementia. Although the pathogenesis of AD remains unknown, the deterioration of the cerebrovascular system constitutes a risk factor associated with the development of the disease. Notably, brain hypoperfusion, a feature of healthy ageing brain and AD, occurs prior to the onset of cognitive decline in AD and correlates with the severity of dementia. Although there is a clear link between hypoperfusion and cognitive alterations in AD, a causal relationship remains to be established. It was hypothesised that chronic cerebral hypoperfusion leads to the accumulation of parenchymal and vascular amyloid-β (Aβ), triggering the development of vascular lesion (microinfarcts (MIs) and haemorrhages) and altering the neurovascular unit (NVU) integrity. Second to this, it was hypothesised that reductions in Aβ levels by immunotherapy targeted to amyloid in young mice, reduce amyloid levels, and prevent vascular lesions improving cognitive performance. Three studies were conducted to test these hypotheses. In the first study, the aim was to characterise age-dependent changes in amyloidrelated pathology in a transgenic mouse model (Tg-SwDI). The temporal amyloid precursor protein (APP) expression, accumulation of parenchymal and cerebrovascular Aβ and Aβ-related microglial and astrocytic activation in the cortex, hippocampus and thalamus of the Tg-SwDI mice at 3, 6 and 9 months of age was compared to wild-type controls. Significantly higher APP expression (p < 0.05), as well as Aβ aggregation (p < 0.001) as the animals aged was found in the Tg-SwDI mice in all the brain regions analysed, which was accompanied by extensive and progressive activation of microglial (p < 0.001) and astrocytic (p < 0.01) cells. These data provided a basis to design the next studies, as it was planned to induce hypoperfusion in these mice before significant Aβ deposition occurs. In the second study, the aim was to investigate the effect of hypoperfusion on Aβ dynamics and subsequently, to study the contribution of hypoperfusion and Aβ pathology to the development of MIs and haemorrhages, and to the potential alteration of astrocyte and tight junction (TJ) integrity. To address this, mild chronic cerebral hypoperfusion was induced in Tg-SwDI and wild-type mice by bilateral common carotid stenosis for 1 and 3 months. A significant increase in soluble Aβ40/42 levels was initially found after 1 month of hypoperfusion in the parenchyma (Aβ40, p = 0.0239; Aβ42 p = 0.0198) in parallel with elevated APP levels and APP proteolytic cleavage products (p < 0.05). Thereafter, following 3 months, a significant increase in insoluble Aβ40/42 levels was determined in the parenchyma (Aβ40, p = 0.0024; Aβ42 p = 0.008) and vasculature (Aβ40, p = 0.0046; Aβ42 p = 0.0118) of Tg-SwDI mice. There was no change in the levels of Aβ co-localised to vessels following 1 month of hypoperfusion; however Aβ levels were significantly increased in cerebral vessels after 3 months (p = 0.0483). The proportion of Aβ containing vessels was significantly higher in the small vessels of the hypoperfused animals compared to sham mice (p < 0.05). MIs associated with microglial proliferation were present in the Tg-SwDI mice and the burden was exacerbated by hypoperfusion at 1 and 3 months (p < 0.05). Significantly higher levels of NADPH Oxidase-2 (NOX2) were found in the transgenic mice compared to the wild-type controls at both time-points analysed (p < 0.05), and this was exacerbated after 1 month of hypoperfusion in the Tg-SwDI mice (p < 0.05). There was a positive correlation between NOX2 and soluble parenchymal Aβ levels (r = 0.6643, p = 0.0019). A minimal effect on the development of haemorrhages at these time-points was observed. In parallel to this, astrocyte activation was significantly higher in the Tg-SwDI mice compared to the wild-type controls at both time-points studied (p < 0.05); however, no effect of hypoperfusion was observed. Also, significantly higher levels of aquaporin-4 (AQP4) in the Tg-SwDI mice compared to the wild-type controls following 1 month of hypoperfusion were found (p < 0.001). There was a positive correlation between AQP4 and soluble parenchymal Aβ levels (r = 0.4735, p = 0.0095). Claudin-5 levels were significantly higher in the Tg-SwDI mice compared to the wild-type controls at both time-points analysed (p < 0.0001), and this was exacerbated following 1 month of hypoperfusion in the transgenic model (p < 0.05). A positive correlation between claudin-5 and vascular Aβ levels was observed (r = 0.6113, p = 0.0004). Together, these data suggest a synergistic contribution of amyloid and hypoperfusion pathologies to the tissue damage and implicate a role of oxidative stress and inflammation. In the third study, the aim was to determine the effects of passive amyloid immunisation on Aβ levels, development of MIs and haemorrhages and behavioural performance in the Tg-SwDI mice. To address this, the mice underwent weekly intraperitoneal injections with either 3D6 or 10D5 antibodies during 3 months. Although there were no significant changes between control and 10D5/3D6 treated mice in amyloid levels, appearance of MIs and cognitive performance, it was noted that there was a trend towards a reduction in amyloid levels and MI area in the 10D5/3D6 treated mice compared to the control animals. Furthermore, there was no evidence of microhaemorrhages in response to the immunisation. These results demonstrate that Aβ immunotherapy with the antibodies 3D6 and 10D5 may potentially decrease parenchymal and vascular amyloid accumulation, reducing the appearance of MIs and notably without triggering the development of microhaemorrhages. Collectively, the findings presented in the current thesis demonstrate that chronic cerebral hypoperfusion increases parenchymal and vascular Aβ levels and point towards a mechanism in which the cascade of events including inflammation and oxidative stress, triggered synergistically by hypoperfusion and Aβ, resulted in the widespread development of MIs and NVU changes which may further induce the alteration of cognition networks. A mixed therapy, aimed at improving cerebrovascular health and targeting the accumulation of Aβ, represents a promising strategy to prevent neurodegenerative processes and further cognitive decline in AD.
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Multidimensional apathy in neurodegenerative diseaseRadakovic, Ratko January 2016 (has links)
Apathy is characterised by a lack of motivation towards goal directed behaviour and is a symptom of various neurodegenerative diseases. There are various tools that can be used to assess apathy but a caveat of these is that they usually assess it as a unidimensional concept. Apathy has been recognised to have a multidimensional substructure. The Dimensional Apathy Scale is the only comprehensive measure designed to quantify neurobiologically-based subtypes, called Executive, Emotional and Initiation apathy. The first aim of this study was to explore multidimensional apathy, and its associations with demographic variables, in healthy, community dwelling adults. Secondly, multidimensional apathy was explored in neurodegenerative diseases, specifically Amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD). For each disease group, the validity and reliability of both the self rated and carer rated DAS were also determined. Finally, the association between specific apathy subtype impairments and executive dysfunction was explored in ALS patients. Four hundred healthy community dwelling adults, eighty-three ALS patients (seventy-five carers), thirty-four PD patients (thirty carers) and forty-nine AD patients (eighty-nine carers) were recruited for the questionnaire study. In the healthy community dwelling adults, Executive apathy decreased with age, whereas Emotional increased with age. Gender differences were also shown with higher apathy in males on Emotional apathy. There were also employment differences, in that Executive apathy was higher in unemployed individuals compared to those who were employed. Emotional apathy showed difference in type of employment, where full time employed individuals were significantly more apathetic than those employed part time. These findings were taken into account in selecting the appropriate control samples to match our patient groups. In the patient groups, ALS patients were found to be significantly more impaired on the Initiation subscale when compared to controls. Furthermore, Initiation apathy was found to be the most frequent impairment above abnormality cut-off on the carer rated DAS. PD patients were significantly more impaired on Executive and Initiation apathy when compared to controls. These two subscales were most frequently above abnormality cut-off in the carer rated DAS. Finally, AD patients were significantly more impaired on all subscales when compared to controls and, on the carer rated DAS, global impairment over all subscales was most often reported as above abnormality cut-off. Additionally in AD, there was a significant disparity between carer and patient ratings on Executive and Initiation apathy, indicating patients’ impaired awareness. When comparing patient groups, there was a significant difference between carer rated apathy subtype impairments for each patient group. Validity and reliability of the DAS was found to be robust when compared to standard measures of apathy and depression. In the experimental study, a sample of ALS patients (and their carers) and healthy controls (and their informants) were recruited to complete a battery of neuropsychological tests, the DAS, other apathy and depression measures. ALS patients were impaired on tasks of executive functioning when compared to controls. Furthermore, apathy subtype deficits were associated with executive dysfunction in ALS. In conclusion, apathy is a multidimensional concept that manifests in different subtype profiles dependent on neurodegenerative disease. This has further implications for understanding and assessment of cognitive dysfunction and neuropsychiatric symptoms, such as apathy, in ALS and other neurodegenerative disease patient groups.
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The interaction between amyloid beta peptide and phospholipidsMa, Xin January 2015 (has links)
The aim of the thesis project was to examine what form(s) of Amyloid beta (Aβ) (25-‐35) peptide interact with phospholipids in vitro and the implications of this for the mechanism of Alzheimer’s Diseases (AD). The mechanism of AD is thought to involve protein folding and misfolding. An increasing amount of evidence has shown that protein misfolding plays an important role in the biological and pathological processes of AD. Although seen as the biomedical markers of those diseases, the roles of amyloid aggregates themselves are still not fully understood. Whether the aggregates, or the monomer, or some other intermediates of Aβ cause AD is still unknown. In order to investigate the membrane-‐interaction of Aβ and its implications for AD, two forms of Aβ, namely levorotary and dextrorotary (L-‐ and D-‐) Aβ isomers were used. Evidence has shown that L-‐ and D-‐ peptide can each form aggregates in a humid environment. However, when mixed together, L-‐ and D-‐ peptides tend not to form any aggregates. Using the mixtures of L-‐ and D-‐ peptides at different proportions and as well as using L-‐ and D-‐ alone can help us to determine the toxic form of Aβ. Phospholipids have been used to mimic membrane bilayers. Biological membranes in vivo are a complicated system. They contain three types of lipids, namely phospholipids, glycolipids, and steroids. Different types of cells and different membranes have different proportions of those lipids. Studying the interaction between Aβ and membranes in vivo can be extremely difficult. Artificial membranes, which only contains one kind of lipids, on the other hand, are a useful tool for the study of molecular interactions. Phospholipids are the most abundant type of membrane lipid and thus that can be seen as representative of cell membranes. The interactions of Aβ and different kinds of phospholipids have been investigated in this project. This thesis discusses the secondary structure of Aβ in different environment, the interaction between Aβ and phospholipids at the air-‐water surface, and the location of Aβ in membranes during the interaction. The study provides useful information of the mechanisms and the origin of AD. At the end of the thesis, a discussion chapter analyses the difficulties of studying Aβ and AD and the potentials and inadequacies of this research.
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The effect of cognitive state on the consolidation of basic and complex memoriesCraig, Michael January 2016 (has links)
Recent research demonstrates that new verbal memories are retained better if learning is followed by a brief period of wakeful rest. This effect is hypothesised to be the result of wakeful rest providing a state that is conducive for early-stage cellular consolidation (i.e. strengthening of specific memory traces) by protecting this process from interfering sensory input and associated encoding. The aims of this PhD project were to (i) examine whether the benefit of wakeful rest extends to the retention of complex spatial memories, and (ii) explore the effects of different cognitive states on memory consolidation. In order to address the first aim, three virtual reality spatial memory experiments were conducted. In young and older adults, wakeful rest not only enhanced the retention of complex spatial memories, but it also promoted the systems-level integration of spatial memories into accurate cognitive maps, a function, hitherto, assumed to be specific to sleep (Chapters 2-4). Pilot work also tentatively suggested that wakeful rest enhances the retention of complex spatial memories (i.e. a recently travelled route) in patients with amnestic Mild Cognitive Impairment (Chapter 4). In order to address the second aim, five experiments were run in young adults. The first experiment directly compared the effects of wakeful rest and sleep, two states that are positively associated with consolidation. Wakeful rest enhanced the retention of a list of known words, whereas a similar-length period of sleep enhanced the acquisition of novel linguistic constraints (Chapter 5). The final four experiments revealed that, similar to continuous external sensory input, internally generated autobiographical thinking activities (recalling the past and imagining the future) interfere with consolidation (Chapter 6). Together, the findings reported in this thesis reveal that wakeful rest promotes the strengthening (cellular consolidation) and wider integration (systems consolidation) of basic and complex declarative memories, and that this effect is contingent on a reduction in external sensory input as well as rich autobiographical thought.
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The potential neuroprotective effects of two South African plant extracts in hydrogen peroxide-induced neuronal toxicityGier, Megan Loran January 2018 (has links)
Magister Scientiae (Medical Bioscience) - MSc(MBS) / Background: Oxidative stress induced by reactive oxygen species has been strongly associated with many neurodegenerative diseases (NDDs) and many medicinal plant-derived products have been reported to exert potent antioxidant properties. Sutherlandia frutescens (SF) and Carpobrotus edulis (CE) are two indigenous South African plants with known anti-inflammatory, anti-bacterial, antioxidant and anti-cancer properties. However, the neuroprotective effects of SF and CE have not been extensively studied.
Aims: This study was done to investigate the neuroprotective potentials of S. frutescens and C. edulis aqueous extracts on hydrogen peroxide (H2O2)-induced toxicity in an SH-SY5Y neuroblastoma cellular model of oxidative stress injury.
Methods: The maximum non-toxic dose (MNTD) of SF and CE against SH-SY5Y cells was determined using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Thereafter, the cells were exposed to 250 μM H2O2 for 3 hours before treatment with the determined MNTDs of SF and CE extracts respectively and the effects of the treatments on caspase-9 protease activity, intracellular ROS levels, mitochondrial membrane permeability (MMP), nitric oxide (NO) activity, intracellular calcium activity and endogenous antioxidant activity in SH-SY5Y cells was evalaluated using caspase activity kits, DCFH-DA assay, rhodamine 123 fluorescent dye, Griess reagent, Fluo-4 direct calcium reagent, Hoechst staining dye, Superoxide dismutase (SOD) colorimetric and Catalase (CAT) assays, respectively.
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THE DEVELOPMENT OF NOVEL PROTEASOME INHIBITORS FOR THE TREATMENT OF MULTIPLE MYELOMA AND ALZHEIMER’S DISEASELee, Min Jae 01 January 2019 (has links)
Over a decade, proteasome inhibitors (PIs), bortezomib, carfilzomib (Cfz) and ixazomib, have contributed to a significant improvement in the overall survival for multiple myeloma (MM) patients. However, the response rate of PI was fairly low, leaving a huge gap in MM patient care. Given this, mechanistic understanding of PI resistance is crucial towards developing new therapeutic strategies for refractory/relapsed MM patients.
In this dissertation work, we found H727 human bronchial carcinoid cells are inherently resistant to Cfz, yet susceptible to other PIs and inhibitors targeting upstream components of the ubiquitin-proteasome system (UPS). It indicated H727 cells may serve as a cell line model for de novo Cfz resistance and remains UPS dependent for survival. To examine the potential link between proteasome catalytic subunit composition and cellular response to Cfz, we altered the composition of proteasome catalytic subunits via interferon-γ treatment or siRNA knockdown in H727 cells. Our results showed alteration in composition of proteasome catalytic subunits results in sensitization of H727 cells to Cfz. It supported that proteasome inhibition by alternative PIs may still be a valid therapeutic strategy for patients with relapsed MM after having received treatment with Cfz. With this in mind, we designed and synthesized a small library of epoxyketone-based PIs by structural modifications at the P1′ site. We observed that a Cfz analog, harboring a hydroxyl substituent at its P1′ position was cytotoxic against cancer cell lines with de novo or acquired resistance to Cfz. These results suggested that peptide epoxyketones incorporating P1′-targeting moieties may have the potential to overcome Cfz resistance mechanisms in cells.
The immunoproteasome (IP), an inducible proteasome variant which is harboring distinct catalytic subunits, LMP2, MECL1 and LMP7 of the proteasome typically expressed in cells of hematopoietic origin, plays a role in immune response and is closely linked to inflammatory diseases. It has been reported that the IP is upregulated in reactive glial cells surrounding amyloid β (Aβ) deposits in brains of Alzheimer’s disease (AD) patients and AD animal models.
To investigate whether the IP is involved in the pathogenesis of AD, we examined the impact of IP inhibition on cognitive function in AD mouse models. We observed that YU102, an epoxyketone peptide targeting the IP catalytic subunit LMP2, improved cognitive dysfunction in AD mice without clearance of Aβ deposition or tau aggregation. Our cell line model study also showed a potential mode of action of YU102 which is suppressing pro-inflammatory cytokine production in microglial cells. It suggested that LMP2 contributes to microglia-mediated inflammatory response. These findings supported that LMP2 may offers a valuable therapeutic target for treatment of Alzheimer’s disease, expanding the therapeutic potential of the LMP2-targeting strategy.
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PRECLINICAL TARGETING OF TREM2 FOR THE TREATMENT OF ALZHEIMER'S DISEASE-TYPE PATHOLOGY IN A TRANSGENIC MOUSE MODELPrice, Brittani Rae 01 January 2019 (has links)
Alzheimer's disease (AD) is defined as a progressive neurodegenerative disorder and is characterized by a devastating mental decline. There are three pathological hallmarks of the disease necessary for its diagnosis, these are extracellular amyloid plaques comprised of the beta-amyloid (Aβ) protein, intracellular neurofibrillary tangles comprised of hyperphosphorylated tau protein, and marked neuronal loss. Active immunization against Aβ1-42 or passive immunization with monoclonal anti-Aβ antibodies has been shown to reduce amyloid deposition and improve cognition in transgenic mouse models of AD, aged beagles, and nonhuman primates. Unfortunately, due to cerebrovascular adverse events, both active and passive immunization strategies targeting Aβ have failed in clinical trials. It is, therefore, necessary to identify novel amyloid-clearing therapeutics that do not induce cerebrovascular adverse events. We hypothesized that neuroinflammatory modulation could be a potential novel target.
Triggering receptor expressed on myeloid cells-2 (TREM2) is a lipid and lipoprotein binding receptor expressed exclusively in the brain by microglia. Homozygous TREM2 loss of function mutations cause early-onset progressive presenile dementia while heterozygous, function-reducing point mutations triple the risk of sporadic, late-onset AD. Heterozygous TREM2 point mutations, which reduce either ligand binding or cell surface expression, are associated with a reduction in the number of microglia surrounding amyloid plaques, microglial inability to phagocytose compact Aβ deposits and form a barrier between plaques and neurons, an increase in the number of phospho- tau-positive dystrophic neurites and increased tau in the cerebrospinal fluid. Heterozygous mutations also double the rate of brain atrophy and decrease the age of AD onset by 3-6 years. Although human genetics supports the notion that loss of TREM2 function exacerbates neurodegeneration, it is unclear whether activation of TREM2 in a disease state is beneficial.
The work we present here characterizes a TREM2 agonizing antibody as a potential therapeutic for amyloid reduction. We found that its administration results in immune modulation, recruitment of microglia to the site of amyloid plaques, reduced amyloid deposition and improvement in spatial learning and novel object recognition memory in the 5xFAD model of AD. More specifically, we show that intracranial injection of TREM2 agonizing antibodies into the frontal cortex and hippocampus of 5xFAD mice leads to clearance of diffuse and compact amyloid. We also show that systemic injection of TREM2 agonizing antibodies weekly over a period of 14 weeks results in clearance of diffuse and compact amyloid as well as elevated plasma concentrations of Aβ1-40 and Aβ1-42. Furthermore, systemic administration of these antibodies led to immune modulation and enhanced cognitive performance on radial arm water maze and novel object recognition tests. Importantly, we show the TREM2 agonizing antibody does not induce the adverse cerebrovascular events known to accompany amyloid modifying therapies. Though systemic administration of both TREM2 agonizing and anti-Abantibodies does not further enhance amyloid clearance or cognitive performance, co-administration mitigates the adverse cerebrovascular events associated with anti-Aβ antibodies.
Collectively, these data indicate TREM2 activators may be an effective therapeutic target for the treatment of AD.
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