TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models

Variants in triggering receptor expressed on myeloid cells 2 (TREM2) confer high risk for Alzheimer’s disease (AD) and other neurodegenerative diseases. However, the cell types and mechanisms underlying TREM2’s involvement in neurodegeneration remain to be established. Here, we report that TREM2 is up-regulated on myeloid cells surrounding amyloid deposits in AD mouse models and human AD tissue. TREM2 was detected on CD45hiLy6C+ myeloid cells, but not on P2RY12+ parenchymal microglia. In AD mice deficient for TREM2, the CD45hiLy6C+ macrophages are virtually eliminated, resulting in reduced inflammation and ameliorated amyloid and tau pathologies. These data suggest a functionally important role for TREM2+ macrophages in AD pathogenesis and an unexpected, detrimental role of TREM2 in AD pathology. These findings have direct implications for future development of TREM2-targeted therapeutics.

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Replacement of brain-resident myeloid cells does not alter cerebral amyloid-β deposition in mouse models of Alzheimer’s disease

Journal of Experimental Medicine ◽

10.1084/jem.20150478 ◽

2015 ◽

Vol 212 (11) ◽

pp. 1803-1809 ◽

Cited By ~ 58

Author(s):

Nicholas H. Varvel ◽

Stefan A. Grathwohl ◽

Karoline Degenhardt ◽

Claudia Resch ◽

Andrea Bosch ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Myeloid Cells ◽

Amyloid Β ◽

Myeloid Cell ◽

Functional Roles ◽

Amyloid Load

Immune cells of myeloid lineage are encountered in the Alzheimer’s disease (AD) brain, where they cluster around amyloid-β plaques. However, assigning functional roles to myeloid cell subtypes has been problematic, and the potential for peripheral myeloid cells to alleviate AD pathology remains unclear. Therefore, we asked whether replacement of brain-resident myeloid cells with peripheral monocytes alters amyloid deposition in two mouse models of cerebral β-amyloidosis (APP23 and APPPS1). Interestingly, early after repopulation, infiltrating monocytes neither clustered around plaques nor showed Trem2 expression. However, with increasing time in the brain, infiltrating monocytes became plaque associated and also Trem2 positive. Strikingly, however, monocyte repopulation for up to 6 mo did not modify amyloid load in either model, independent of the stage of pathology at the time of repopulation. Our results argue against a long-term role of peripheral monocytes that is sufficiently distinct from microglial function to modify cerebral β-amyloidosis. Therefore, myeloid replacement by itself is not likely to be effective as a therapeutic approach for AD.

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Role of Endoplasmic Reticulum Stress in Learning and Memory Impairment and Alzheimer's Disease-Like Neuropathology in the PS19 and APPSwe Mouse Models of Tauopathy and Amyloidosis

eNeuro ◽

10.1523/eneuro.0025-17.2017 ◽

2017 ◽

Vol 4 (4) ◽

pp. ENEURO.0025-17.2017 ◽

Cited By ~ 14

Author(s):

Denise Isabelle Briggs ◽

Erwin Defensor ◽

Pooneh Memar Ardestani ◽

Bitna Yi ◽

Michelle Halpain ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Endoplasmic Reticulum ◽

Endoplasmic Reticulum Stress ◽

Learning And Memory ◽

Mouse Models ◽

Memory Impairment

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TRANSGENIC MOUSE MODELS OF ALZHEIMER’S DISEASE

Innovation in Aging ◽

10.1093/geroni/igz038.3077 ◽

2019 ◽

Vol 3 (Supplement_1) ◽

pp. S835-S835

Author(s):

Charnae A Henry-Smith ◽

Xianlin Han

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Mouse Models ◽

Myelin Sheath ◽

Thinking Skills ◽

Drug Dosage ◽

Whole Body ◽

To Receive ◽

The Brain

Abstract Alzheimer’s disease is a progressive brain disease that slowly destroys memory and thinking skills. Alzheimer’s is characterized by an increase in Aβ plaques , and tau tangles. Neurons in the brain have axons covered in myelin sheath that connect microglia and astrocytes. The myelin sheath is composed of about 70% lipid composition; Sulfatide contributing to 30% overall. Sulfatide changes the morphology of primary microglia to their activated form. To study the role of microglia activation and sulfatide levels, three different mouse models were created: APP KI mice, CST Whole Body Ko mice, and cCST (conditional) KO. In order to create the genotype of the APP KI mice, a breeding mouse line was created. The APP KI gene had to be introduced in Plp1-Cre and cCST KO crossed mice to receive a working mouse model. During the duration of breeding for the APP KI mice, a preliminary experiment was performed on the CST KO mice. These mice were given the PLX3397 diet with the aim to remove the microglia and to see the effect of Aβ plaques. The PLX3397 will reduce the microglia targeting the CSF1R. After consuming the diet, the mice were harvested to collect tissues from the brain and spinal cord. Lipidomics and immunohistology were performed. In conclusion, we will continue the breeding of the CST flox/flox / Plp1-Cre / APP KI mice, and the drug dosage and treatment to be used in our APP KI mice will be based on preliminary data from our CST mice.

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Genome research in pre-dementia stages of Alzheimer's disease

Expert Reviews in Molecular Medicine ◽

10.1017/erm.2016.12 ◽

2016 ◽

Vol 18 ◽

Cited By ~ 9

Author(s):

Sonia Moreno-Grau ◽

Agustín Ruiz

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Late Onset ◽

Subjective Cognitive Decline ◽

Genetic Profile ◽

Amyloid Deposits ◽

Dementia Risk ◽

Meta Analyses ◽

Brain Insults

Genetic characterization of individuals at risk of Alzheimer's disease (AD), i.e. people having amyloid deposits in the brain without symptoms, people suffering from subjective cognitive decline (SCD) or mild cognitive impairment (MCI), has spurred the interests of researchers. However, their pre-dementia genetic profile remains mostly unexplored. In this study, we reviewed the loci related to phenotypes of AD, MCI and SCD from literature and performed the first meta-analyses evaluating the role of apolipoprotein E (APOE) in the risk of conversion from a healthy status to MCI and SCD. For AD dementia risk, an increased number of loci have been identified; to date, 28 genes have been associated with Late Onset AD. In MCI syndrome,APOEis confirmed as a pheno-conversion factor leading from MCI to AD, and clusterin is a promising candidate. Additionally, our meta-analyses revealedAPOEas genetic risk factor to convert from a healthy status to MCI [OR = 1.849 (1.587–2.153);P = 2.80 × 10−15] and to a lesser extent from healthy status to SCD [OR = 1.151 (1.015–1.304);P = 0.028]. Thus, we believe that genetic studies in longitudinal SCD and MCI series may provide new therapeutic targets and improve the existing knowledge of AD. This type of studies must be completed on healthy subjects to better understand the natural disease resistance to brain insults and neurodegeneration.

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he amyloid hypothesis of Alzheimer's disease: past and present, hopes and disappointments

Neurology neuropsychiatry Psychosomatics ◽

10.14412/2074-2711-2019-3-4-10 ◽

2019 ◽

Vol 11 (3) ◽

pp. 4-10

Author(s):

I. V. Litvinenko ◽

A. Yu. Emelin ◽

V. Yu. Lobzin ◽

K. A. Kolmakova ◽

K. M. Naumov ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Signs ◽

Passive Immunization ◽

Amyloid Hypothesis ◽

Amyloid Deposits ◽

Redox Active ◽

Protein Overproduction ◽

The Brain

In 1887, S.A. Belyakov, a physician of the Imperial Medical and Surgical Academy, first described amyloid deposits in the brain of patients with dementia. Later, in 1906, A. Alzheimer revealed amyloid plaques and tau tangles in a patient with clinical signs of dementia. Over the following 100 years, the development of the concept of the amyloid origin of Alzheimer's disease (AD) confirmed numerous relationships between the brain accumulation of APs and cognitive decline. And if at the beginning of the amyloid era many researchers considered that the disease was caused by amyloid beta (Aβ) protein overproduction, in recent years they have increasingly pointed to a defect in the mechanisms of Aβ clearance, especially after the discovery of the lymphatic system of the brain. The role of disturbed homeostasis of redox-active metals, primarily iron and copper, in the development of the disease is also considered.The amyloid hypothesis of AD has served as the basis for several areas in the design of drugs, such as secretase inhibitors, immunomodulatory drugs for active and passive immunization. However, only one drug (Akatinol memantine, an inhibitor of NMDA receptors and glutamatergic excitotoxicity) for the treatment of AD has been introduced into clinical practice over the past 20 years. Of interest are the data obtained in new studies of Akatinol memantine, which suggest that the latter is able to some extent affect the main pathophysiological processes underlying the development of cognitive impairment in Alzheimer-type pathology.

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The role of impairment of higher mental functions in suicidogenesis in the dementia caused by Alzheimer's disease

Psychosomatic Medicine and General Practice ◽

10.26766/pmgp.v3i3.104 ◽

2018 ◽

Vol 3 (3) ◽

pp. e0303104

Author(s):

Iryna Mudrenko

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

High Risk ◽

Suicidal Behavior ◽

Control Group ◽

Elderly Age ◽

Mental Functions ◽

Age Related ◽

Higher Mental Functions

Background Dementia is the age-related disease. At the same time, the elderly age has one of the peaks in the number of suicides. Psychology of patients with demetia is characterized by the feeling of hopelessness, pessimism, awareness of own insolvency, dependence on others, that affects the risk of suicide. It is established that the highest risk of suicide in the early stages of dementia with the progression of cognitive deficit, the risk of suicide decreases. Aim To study the role of impairment of higher mental functions (perception, reasoning, attention, memory, emotions, will, speech) in the formation of suicidal behaviour in patients with dementia in Alzheimer's disease. Materials and methods There were examined 75 patients with dementia in Alzheimer's disease, 36 patients with a history of suicidal behavior composed the main group, and 39 patients without the signs of suicidal behavior composed control group. The study was carried out using clinical-anamnestic, psychopathological methods and mathematical statistical methods. Results The high risk of suicide in dementia caused by Alzheimer's disease is combined with the inhibition of thinking, the delusional ideas of self-blame and self-effacement (p ≤ 0.05); depressed mood, inner agitation, anxiety, feeling of despair, hopelessness, guilt, melancholia, apathy (p ≤ 0.05); effector-volitional disorders in the form of hypobulia, hypokinesia, hypomimia, decreased libido (p ≤ 0.05); speech disturbance in the form of bradylalia p ≤ 0.05; greater exhaustion and decreased attention (p ≤ 0.05). On the contrary, the following peculiarities of higher mental functions, namely thought disorder are referred to the anti-risk factors of suicide in dementia caused by Alzheimer's disease: the delusional ideas of relation and damage (p ≤ 0.05); emotions: the feeling of fear (p ≤ 0.05); effector-volitional sphere: parabulia and hyperkinesia (p ≤ 0.05). Conclusion On the basis of clinical and psychopathological study of patients with dementia in Alzheimer's disease, the specific impairment of higher mental functions and emotional-volitional spheres reasoning, memory, attention, perception, speech, emotions) are identified associated with high risk of suicide.

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