A Shotgun Proteomic Platform for a Global Mapping of Lymphoblastoid Cells to Gain Insight into Nasu-Hakola Disease

Nasu-Hakola Disease (NHD) is a recessively inherited systemic leukodystrophy disorder characterized by a combination of frontotemporal presenile dementia and lytic bone lesions. NHD is known to be genetically related to a structural defect of TREM2 and DAP12, two genes that encode for different subunits of the membrane receptor signaling complex expressed by microglia and osteoclast cells. Because of its rarity, molecular or proteomic studies on this disorder are absent or scarce, only case reports based on neuropsychological and genetic tests being reported. In light of this, the aim of this paper is to provide evidence on the potential of a label-free proteomic platform based on the Multidimensional Protein Identification Technology (MudPIT), combined with in-house software and on-line bioinformatics tools, to characterize the protein expression trends and the most involved pathways in NHD. The application of this approach on the Lymphoblastoid cells from a family composed of individuals affected by NHD, healthy carriers and control subjects allowed for the identification of about 3000 distinct proteins within the three analyzed groups, among which proteins anomalous to each category were identified. Of note, several differentially expressed proteins were associated with neurodegenerative processes. Moreover, the protein networks highlighted some molecular pathways that may be involved in the onset or progression of this rare frontotemporal disorder. Therefore, this fully automated MudPIT platform which allowed, for the first time, the generation of the whole protein profile of Lymphoblastoid cells from Nasu-Hakola subjects, could be a valid approach for the investigation of similar neurodegenerative diseases.

The Role of White Matter Dysfunction and Leukoencephalopathy/Leukodystrophy Genes in the Aetiology of Frontotemporal Dementias: Implications for Novel Approaches to Therapeutics

Frontotemporal dementia (FTD) is a common cause of presenile dementia and is characterized by behavioural and/or language changes and progressive cognitive deficits. Genetics is an important component in the aetiology of FTD, with positive family history of dementia reported for 40% of cases. This review synthesizes current knowledge of the known major FTD genes, including C9orf72 (chromosome 9 open reading frame 72), MAPT (microtubule-associated protein tau) and GRN (granulin), and their impact on neuronal and glial pathology. Further, evidence for white matter dysfunction in the aetiology of FTD and the clinical, neuroimaging and genetic overlap between FTD and leukodystrophy/leukoencephalopathy are discussed. The review highlights the role of common variants and mutations in genes such as CSF1R (colony-stimulating factor 1 receptor), CYP27A1 (cytochrome P450 family 27 subfamily A member 1), TREM2 (triggering receptor expressed on myeloid cells 2) and TMEM106B (transmembrane protein 106B) that play an integral role in microglia and oligodendrocyte function. Finally, pharmacological and non-pharmacological approaches for enhancing remyelination are discussed in terms of future treatments of FTD.

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Background Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia. Methods To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2−/− mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches. Results While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2−/− mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2−/− mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Trem2 Y38C mutation and loss of Trem2 impairs neuronal synapses in adult mice

Background: Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and Nasu Hakola Disease (NHD). The Trem2 variant R47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linked Trem2 variants like Y38C, are associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2 species, predisposes individuals to presenile dementia.Methods: To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38C/Y38C and Trem2-/- mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results: While mice harboring the Trem2 Y38C exhibited normal expression levels of TREM2, the pathological outcomes phenocopied Trem2-/- mice at 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion: Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38C and Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like amyloid. This suggests TREM2 impacts neuronal functions providing molecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Trem2 Y38C Mutation and Loss of Trem2 Impairs Neuronal Synapses in Adult Mice

Background:Triggering receptor expressed on myeloid cells 2 (TREM2) is expressed in the brain exclusively on microglia and genetic variants are linked to neurodegenerative diseases including Alzheimer’s disease (AD), frontotemporal dementia (FTD) and NasuHakola Disease (NHD). The Trem2 variantR47H, confers substantially elevated risk of developing late onset Alzheimer’s disease, while NHD-linkedTrem2 variants like Y38Care associated with development of early onset dementia with white matter pathology. However, it is not known how these Trem2species predispose individuals to presenile dementia.Methods:To investigate if Trem2 Y38C or loss of Trem2 alters neuronal function, we generated a novel mouse model to introduce the NHD Trem2 Y38C variant in murine Trem2 using CRISPR/Cas9 technology. Trem2Y38/Y38C and Trem2-/-mice were assessed for Trem2 expression, differentially expressed genes, synaptic protein levels and synaptic plasticity using biochemical, electrophysiological and transcriptomic approaches.Results:While mice harboring Trem2 Y38C exhibited normal expression levels of Trem2, the pathological outcomes phenocopied Trem2-/- miceat 6 months. Transcriptomic analysis revealed altered expression of neuronal and oligodendrocytes/myelin genes. We observed regional decreases in synaptic protein levels, with the most affected synapses in the hippocampus. These alterations were associated with reduced synaptic plasticity. Conclusion:Our findings provide in vivo evidence that Trem2 Y38C disrupts normal TREM2 functions. Trem2Y38C/Y38Cand Trem2-/- mice demonstrated altered gene expression, changes in microglia morphology, loss of synaptic proteins and reduced hippocampal synaptic plasticity at 6 months in absence of any pathological triggers like tau or amyloid. This suggests TREM2 impacts neuronal functions and providesmolecular insights on the predisposition of individuals with TREM2 variants resulting in presenile dementia.

Identifying People with Dementia in Electronic Primary Care Records in the UK

Background Many epidemiological questions need to be answered regarding dementia, including the causes, prognosis, comorbidities, and treatment of the condition and complications. A routine electronic primary care dataset provides a way of investigating some of the complicated factors with rich information. However, there has been concern regarding whether dementia is recorded well enough. Methods This study has therefore explored this by conducting a systematic review to understand how dementia has been identified previously in primary care databases in the UK, and added to this by exploring additional terms and symptoms, and medications that might be helpful in identifying people with dementia. The study estimated the prevalence and incidence rates of dementia in The Health Improvement Network (THIN) database and compared with other longitudinal studies using the comprehensive list of diagnostic codes. Results The estimated incidence rates per 1,000 person-years for the 60+ age group who had any of the first diagnosis among the Quality Outcomes Framework (QOF) defined codes, Other diagnoses, Dementia symptoms and Prescribed medications were 2.5, 4.7, and 15.9 in 1995, 2004, and 2015 respectively. The estimated prevalence were 2.8, 3.2, and 10.2 in 1995, 2004, and 2015 respectively. Conclusions The codes related to dementia symptoms (represented by mini-mental state examination, the six item cognitive impairment test, referral to memory clinic and behaviour assessment) seem to cover a broad definition of dementia or pre-existing dementia population in the UK primary care records. At least, using of the Other diagnoses (represented by dementia annual review, senile/presenile dementia and dementia monitoring) in addition to the QOF defined codes, and Prescribed medications were evidenced that will not missing out a number of people with dementia. Key messages The codes related to dementia symptoms seem to cover a broad definition of dementia or pre-existing dementia population in electronic primary care records in the UK. Nevertheless, the codes about non-specific or temporary symptoms may need to be used carefully as it is possible for memory or cognitive function to be impaired temporarily due to other factors.

Frontotemporal dementia in psychiatric practice: diagnostic and therapeutic aspects

Frontotemporal dementia (FTD) is a progressive neurodegenerative disorder. It begins usually in the presenile age and affects predominantly the frontal lobes and anterior temporal lobes of the brain. Currently, there are three main clinical variant of FTD: behavioral variant frontotemporal dementia (bvFTD), which manifests early with behavioral and executive impairments; primary progressive aphasia (PPA), in which progressive speech disorders, grammatical, and verbal production; semantic variant primary progressive aphasia (svPPA). In psychiatric practice, patients with FTD occur not so rarely that requires a differential diagnosis with an endogenous mental disease and presenile dementia, especially with Alzheimer’s disease (AD). Te importance of correct diagnosis is determined by differences in the treatment of patients with dementia. In FTD, in contrast to patients with AD, the appointment of acetylcholinesterase inhibitors does not lead to a benefcial therapeutic effect and, therefore, is not appropriate. Te use of memantine, especially in the moderatesevere stages of FTD, can be useful to treat noncognitive symptoms. In the standard therapy of patients with bvFTD, should be included recommendations for the antipsychotic or the use of SSRI antidepressants, for correction of affective and behavioral disorders.