Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease

Perez, Sylvia E.; Nadeem, Muhammad; He, Bin; Miguel, Jennifer C.; Malek-Ahmadi, Michael; Chen, Kewei; Mufson, Elliott J.

doi:10.1016/j.neurobiolaging.2017.02.012

Cited by 42 publications

(39 citation statements)

References 58 publications

(99 reference statements)

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“…Our observations are consistent with: (i) the original study of the characterization of TREM2 in human immature monocyte‐derived dendritic cells , (ii) the findings in one control and one AD case using the same antibody in the previous study assessing the sensitivity of TREM2 antibodies by Western blot followed for the HPA010917 antibody by immunohistochemistry after preabsorption with the recombinant protein to confirm the specificity , (iii) with the detection of TREM2 expression in in monocyte‐derived macrophages but not microglia in APP/PS1 mice , and (iv) the absence of association between TREM2 and Iba1 protein levels detected by Western blots in human frontal cortex . Our findings are also in accord with the proposed role of TREM2 as regulator of phagocytosis, as the brain parenchymal cells labelled in this study are indeed performing a phagocytic function in clearing necrotic tissue debris in infarcts.…”

Section: Discussionmentioning

confidence: 99%

TREM2 expression in the human brain: a marker of monocyte recruitment?

et al. 2017

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Mutation in the triggering receptor expressed on myeloid cells (TREM) 2 gene has been identified as a risk factor for several neurodegenerative diseases including Alzheimer's disease (AD). Experimental studies using animal models of AD have highlighted a number of functions associated with TREM2 and its expression by microglial cells. It has therefore been assumed that this is also the case in humans. However, there is very limited information concerning the cellular expression of TREM2 in the human brain. As part of investigations of microglia using post‐mortem resources provided by the Medical Research Council Cognitive Function and Ageing Studies (MRC‐CFAS), we immunostained the cerebral cortex of 299 participants for TREM2 using the Sigma antibody HPA010917 and compared with the macrophage/microglial markers Iba1 and CD68. As expected, Iba1 and CD68 labeled microglia and perivascular macrophages. However, in most cases (284/299), the TREM2 antibody labelled monocytes within vascular lumens, but not microglia or perivascular macrophages. In contrast, in 5 out of 6 cases with acute infarcts, TREM2 immunoreaction identified cells within the brain parenchyma interpreted as recruited monocytes. Six cases with old infarcts contained phagocytic foamy macrophages which were CD68‐positive but TREM2 negative. Our observations, using the HPA010917 anti‐TREM2 antibody, suggest that TREM2 is not expressed by microglia but instead seems to be a marker of recruited monocytes in the human brain. This finding has implications with regards to the role of TREM2 as a risk factor, emphasizing the importance of systemic immune responses in the development and progression of Alzheimer's disease.

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Section: Discussionmentioning

confidence: 99%

TREM2 expression in the human brain: a marker of monocyte recruitment?

et al. 2017

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“…Additional genes which have been reported as possible risk factors include glyceraldehyde-3-phosphate dehydrogenase (GAPDH) [5], a rare variant of the triggering receptor expressed on myeloid cells 2 (TREM2) gene [161], genetic variation in the estrogen receptor (ESR) gene [162], polymorphisms of the clusterin gene [150], and the transferrin (Tf) gene [194]. The TREM2 gene is involved in triggering receptor expression on myeloid cells, and upregulation of the gene has been demonstrated in frontal cortex but not in the HC in SAD [146].…”

Section: Apoementioning

confidence: 99%

Risk factors for Alzheimer’s disease

Armstrong¹

2019

361

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Early reviews identified over 20 risk factors associated with Alzheimer's disease (AD) including age, familial inheritance, exposure to aluminium, traumatic brain injury (TBI), and associated co-morbidities such as vascular disease and infection. In the light of recent evidence, this review reconsiders these risk factors, identifies those currently regarded as important, and discusses various hypotheses to explain how they may cause AD. Rare forms of early-onset familial AD (EO-FAD) are strongly linked to causal gene mutations, viz. mutations in amyloid precursor protein (APP) and presenilin (PSEN1/2) genes. By contrast, late-onset sporadic AD (LO-SAD) is a multifactorial disorder in which age-related changes, genetic risk factors, such as allelic variation in apolipoprotein E (Apo E) and many other genes, vascular disease, TBI and risk factors associated with diet, the immune system, mitochondrial function, metal exposure, and infection are all implicated. These risk factors may act collectively to cause AD pathology: 1) by promoting the liberation of oxygen free radicals with age, 2) via environmental stress acting on regulatory genes early and later in life ('dual hit' hypothesis), or 3) by increasing the cumulative 'allostatic load' on the body over a lifetime. As a consequence, lifestyle changes which reduce the impact of these factors may be necessary to lower the risk of AD.

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“…Clinical neuropsychological testing included Mini-Mental State Examination, global cognitive score, composite zscore compiled from 19 cognitive tests [61], and z-scores from episodic memory, semantic memory, working memory, perceptual speed, and visuospatial tests. Postmortem neuropathology was performed as reported previously [15,[49][50][51]53], which included Braak staging [62], NIA-Reagan criteria [63], and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) [64]. A board-certified neuropathologist excluded cases with other pathologies (e.g., cerebral amyloid angiopathy, vascular dementia, dementia with Lewy bodies, hippocampal sclerosis, Parkinson's disease, and large strokes) and those treated with acetylcholinesterase inhibitors.…”

Section: Clinical and Neuropathological Characteristicsmentioning

confidence: 99%

“…FC (Brodmann's area 10) CHI3L1, CHI3L2, NPTX2, GFAP, C1q, Iba1, and CD44 protein levels were measured in 15 NCI, 15 MCI, 13 mAD, and 7 sAD samples [15]. Briefly, frozen samples were homogenized (150 mg/mL) in phosphate buffer containing protease inhibitors (Sigma, St. Louis, MO) and denatured in SDS loading buffer to a final concentration of 5 mg/ml.…”

Section: Western Blottingmentioning

confidence: 99%

“…AD is pathologically characterized by the accumulation of amyloid-beta (Aβ) plaques, tau neurofibrillary tangles (NFTs), synaptic and neuronal loss, glial activation, and neuroinflammation [6][7][8][9][10][11]. Aβ plaques and NFTs induce an immune response associated with astroglia and microglia activation and increased inflammatory mediators, tumor necrosis factor α [12], S100, interleukin 1 [13,14], such as triggering receptor expressed on myeloid cells 2 (TREM2) [15,16], and complement activation (C1q to C5b-9) [17] in AD [18][19][20]. Recently, the chitinase family of inflammatory proteins, particularly chitinase 3-like 1 (CHI3L1, YKL-40, or HC gp-39), chitinase 3-like 2 (CHI3L2 or YKL- 39), and pentraxin II (NPTX2 or Narp), a member of the pentraxin family, has been associated with AD pathogenesis [21,22].…”

Section: Introductionmentioning

confidence: 99%

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Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

Moreno‐Rodríguez

Perez

Nadeem

et al. 2020

J Neuroinflammation

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Background: Chitinase 3-like 1 (CHI3L1), chitinase 3-like 2 (CHI3L2), and neuronal pentraxin II (NPTX2) are inflammatory biomarkers of Alzheimer's disease (AD). Although studies have demonstrated that cerebrospinal fluid levels of these proteins are changed in AD, no studies have undertaken a detailed examination of alterations in protein levels, cellular expression, and interaction with amyloid in the brain during the progression of AD. Methods:The study evaluated levels of both CHI3L1 and CHI3L2, NPTX2, ionized calcium-binding adapter molecule 1 (Iba1), complement component 1q (C1q), glial fibrillary acidic protein (GFAP), and CD44, in the frontal cortex of people who died with an antemortem clinical diagnosis of no cognitive impairment (NCI), mild cognitive impairment (MCI), mild/moderate AD (mAD), and severe AD (sAD) using immunoblot and immunohistochemical techniques.Results: CHI3L1-immunoreactive (-ir) astrocyte numbers were increased in the frontal cortex and white matter in sAD compared to NCI. On the other hand, increases in GFAP and Iba1-ir cell numbers were observed in MCI compared to NCI but only in white matter. Western blot analyses revealed significantly lower frontal cortex CHI3L2 levels, whereas CD44 levels were increased in sAD. No significant differences for CHI3L1, GFAP, C1q, and NPTX2 protein levels were detected between clinical groups. Strong significant correlations were found between frontal cortex CHI3L1 and Iba1-ir cell numbers in white matter and CHI3L1 and C1q protein levels in the early stages of the disease. C1q and Iba1, CD44 with CHI3L2, and GFAP protein levels were associated during disease progression. CHI3L1 and Iba1 cell numbers in white matter showed a significant associations with episodic memory and perceptual speed.Conclusions: White matter CHI3L1 inflammatory response is associated with cognitive impairment early in the onset of AD.

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Neocortical and hippocampal TREM2 protein levels during the progression of Alzheimer's disease

Cited by 42 publications

References 58 publications

TREM2 expression in the human brain: a marker of monocyte recruitment?

TREM2 expression in the human brain: a marker of monocyte recruitment?

Risk factors for Alzheimer’s disease

Frontal cortex chitinase and pentraxin neuroinflammatory alterations during the progression of Alzheimer’s disease

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