Inflammation, Aβ deposition, and neurofibrillary tangle formation as correlates of Alzheimer's disease neurodegeneration
Abstract
We evaluated entorhinal cortex and superior frontal gyrus for hallmarks of Alzheimer's disease (AD) pathology, including inflammation, in three patient sets: AD patients, nondemented elderly patients with few or no neurofibrillary tangles (NFTs) and amyloid β peptide (Aβ) deposits, i.e. normal controls (NC), and nondemented elderly patients with profuse entorhinal cortex NFTs and neocortical Aβ deposits, i.e. high pathology controls (HPC). Membrane attack complex (C5b-9) immunoreactivity and immune activation of microglia (MHCII expression) were used as general markers for inflammation. Compared to NC patients, AD patients exhibited significant cortical synapse loss, Aβ deposition, NFT formation, and inflammation. HPC patients also had significantly elevated Aβ deposition and NFT formation, but there was no evidence of synapse loss and little or no evidence of inflammation. Across patients and brain regions the measures of inflammation each accounted for significant percentages of the variance in synaptophysin immunoreactivity and each was more highly correlated with synapse estimates than NFT formation or Aβ deposition.
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Increased major histocompatibility complex II staining, counts or expression was noted in the entorhinal cortex, frontal and temporal gyri, hippocampus, and frontal, temporal and occipital cortices.
“Increased MHCII staining, counts or expression was noted in: the entorhinal cortex,7, 18, 20, 35, 43, 47 frontal and temporal gyri,7, 19, 24, 32, 33, 39, 45, 56 hippocampus20, 25, 27, 30, 32, 33, 34, 35, 36, 37, 38, 40, 42, 43, 44, 47 and frontal,18, 21, 25, 40, 41, 44, 46, 48, 49, 52 temporal16, 17, 18, 28, 30, 35, 43, 44, 48, 52 and occipital cortices.25, 35, 41, 43, 44”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
The Histochemistry and Immunohistochemistry section (p. 2) identifies the examined regions as the entorhinal cortex and superior frontal gyrus. The Inflammation section (p. 3) reports higher LN3-positive microglial staining in Alzheimer’s disease patients, with no significant difference between those two regions. This supports the claim for the examined regions, but not for the temporal gyri, hippocampus, or temporal and occipital cortices. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMajor histocompatibility complex II was higher in Alzheimer's disease relative to nonneurological aged controls in 36 of 43 studies.
“major histocompatibility complex II (36/43 studies)”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
The Inflammation results (p. 3) report higher MHC II–marked microglial activity in the Alzheimer's group than in normal aged controls. But this paper compares patient groups, not 43 studies, and does not report a 36/43 finding. (LLM, conf=0.90)
Experimental — accuracy not yet measuredElevations in neuroinflammatory markers are widely reported in Alzheimer's disease in animal models and human subjects.
“Elevations in neuroinflammatory markers are widely reported in Alzheimer’s disease (AD), both in animal models1, 2, 3 and human subjects.4, 5, 6, 7”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
Five of the nine studies comparing microglial markers between AD and high pathology control group reported higher levels of microglia markers in AD, three using HLA-DR, one using CD68, and one using both TREM2 and Iba1.
“Five of these studies reported higher levels of microglia markers in AD, three using HLA-DR,7, 33, 40 one using CD68,83 and one using both TREM2 and Iba1.61”
From Markers of microglia in post-mortem brain samples from patients with Alzheimer’s disease: a systematic review (2018) · cites this paper as [7]
Counts of the various elements were recorded by an observer blind to disease state.
“As in our previous research, 5 counts of the various elements at ϫ100 final magnification were recorded by an observer blind to disease state.”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
HPC patients show little or no evidence of neocortical or limbic synapse loss.
“We have also found that HPC patients show little or no evidence of neocortical or limbic synapse loss, 5 underscoring the critical relationship of neuritic degeneration to dementia.”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
HPC patients had significantly higher (>36%) synaptophysin immunoreactivity on Western blot analysis compared with AD patients, whereas they did not differ from ND patients (7% difference).
“As in our previous study, 5 HPC patients had significantly higher (Ͼ36%) synaptophysin immunoreactivity on Western blot analysis compared with AD patients (F 1,14 ϭ 25.8, P Ͻ 0.0003), whereas they did not differ from ND patients on this measure (F 1,14 ϭ 1.9, P Ͼ 0.50, 7% difference; Table 1).”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
Nearly identical results were obtained in the authors' previous research with six other HPC patients.
“Nearly identical results were obtained in our previous research with six other HPC patients.5”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
Similar results on brain regional changes in AD pathology were obtained in the authors' previous study of ND, HPC, and AD patients.
“Similar results on brain regional changes in AD pathology were obtained in our previous study of ND, HPC, and AD patients.5”
From Soluble Amyloid β Peptide Concentration as a Predictor of Synaptic Change in Alzheimer's Disease (1999) · cites this paper as [5]
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Research works printed but not linked: 21
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Microglia, amyloid and dementia in Alzheimer disease
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Merino-Serrais, P., Benavides-Piccione, R., Blazquez-Llorca, L., Kastanauskaite, A., Rábano, A., Avila, J., & DeFelipe, J. (2013) · Brain · doi:10.1093/brain/awt088 · Cited by 134 · see citing works
“Indeed, there are studies suggesting a strong correlation between the loss of synaptic markers and the presence of neurofibrillary tangles (Terry et al., 1991; Honer et al., 1992; Masliah et al., 1992; Wakabayashi et al., 1994; Lue et al., 1996; Samuel et al., 1997; Heffernan et al., 1998).”
BackgroundGrammas, P., & Ovase, R. (2002) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)61105-4 · Cited by 134 · see citing works
Neuroinflammation in Alzheimer’s Disease
Reinisch, V. M., Krause, D., & Müller, N. (2014) · Springer eBooks · doi:10.1007/978-1-4939-1071-7_9 · Cited by 140 · see citing works
Activated microglia in dementia with Lewy bodies
Mackenzie, I. R. (2000) · Neurology · doi:10.1212/wnl.55.1.132 · Cited by 126 · see citing works
Walker, J., & Harrison, F. E. (2015) · Nutrients · doi:10.3390/nu7095341 · Cited by 127 · see citing works
Epigenomics of Alzheimer's disease
Bennett, D. A., Yu, L., Yang, J., Srivastava, G. P., Aubin, C., & Jager, P. L. D. (2014) · Translational research · doi:10.1016/j.trsl.2014.05.006 · Cited by 124 · see citing works
Paasila, P. J., Davies, D., Kril, J. J., Goldsbury, C. S., & Sutherland, G. T. (2019) · Brain Pathology · doi:10.1111/bpa.12717 · Cited by 119 · see citing works
“Microglial activation has been considered a key pathomechanism in AD, with activated microglia associating with neuritic plaques and subsequently producing a neurotoxic milieu that contributes to neuronal degeneration (30, 41, 46).”
BackgroundSynaptic Elimination in Neurological Disorders
Cardozo, P. L., de Lima, I. B. Q., Maciel, E. M. A., Silva, N. C., Dobránsky, T., & Ribeiro, F. M. (2019) · Current Neuropharmacology · doi:10.2174/1570159x17666190603170511 · Cited by 113 · see citing works
“The presence of the membrane attack complex (MAC) and the immune activation of microglia have been shown to be better correlated with the number of synapses than the load of neurofibrillary tangles and Aβ deposition [192].”
BackgroundDendritic and Synaptic Pathology in Experimental Autoimmune Encephalomyelitis
Zhu, B., Luo, L., Moore, G. R. W., Paty, D. W., & Cynader, M. S. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)64298-8 · Cited by 119 · see citing works
“It has been shown that presynaptic protein loss and inflammation are co-localized in Alzheimer’s lesions, but both are absent in amyloid-deposited brain areas in nondemented seniors.(46) Consistent with this, dendritic and synaptic damage have been reported in HIV enFigure 7.”
BackgroundVitamin D3 alters microglia immune activation by an IL-10 dependent SOCS3 mechanism
Boontanrart, M. Y., Hall, S. D., Spanier, J. A., Hayes, C. E., & Olson, J. K. (2016) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2016.01.015 · Cited by 123 · see citing works
“patients with similar amounts of plaques in the brain (Lue et al., 1996; Lue et al., 1999).”
Excitatory-inhibitory imbalance in Alzheimer's disease and therapeutic significance
Varela, E. V., Etter, G., & Williams, S. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.04.010 · Cited by 116 · see citing works
Complement activation in very early Alzheimer disease
Zanjani, H., Finch, C. E., Kemper, C., Atkinson, J., McKeel, D., Morris, J. C., & Price, J. L. (2005) · Alzheimer Disease & Associated Disorders · doi:10.1097/01.wad.0000165506.60370.94 · Cited by 115 · see citing works
“Alzheimer disease (AD) is a slow neurodegenerative process with symptoms typically progressing for 10 years.1 Postmortem studies of community living elderly, who were longitudinally evaluated by the Clinical Dementia Rating (CDR 0 to 3), indicate several early stages of AD.1–4 The CDR 0 stage (nondemented, healthy eld…”
BackgroundInfluentialDetection of complement alternative pathway mRNA and proteins in the Alzheimer’s disease brain
Strohmeyer, R., Shen, Y., & Rogers, J. (2000) · Molecular Brain Research · doi:10.1016/s0169-328x(00)00149-2 · Cited by 114 · see citing works
Self-citationDodel, R. C., Du, Y., Bales, K. R., Gao, F., & Paul, S. M. (1999) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1999.0731453.x · Cited by 114 · see citing works
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The role of complement in Alzheimer’s disease pathology
Emmerling, M. R., Watson, M. D., Raby, C. A., & Spiegel, K. (2000) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/s0925-4439(00)00042-9 · Cited by 108 · see citing works
Resistance to Alzheimer's pathology is associated with nuclear hypertrophy in neurons
Riudavets, M. A., Iacono, D., Resnick, S. M., O’Brien, R., Zonderman, A. B., Martin, L. J., Rudow, G., Pletnikova, O., & Troncoso, J. C. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.05.005 · Cited by 106 · see citing works
“The motivation for the present study was to search for morphometric parameters underlying the resilience to AD in cognitively normal subjects with substantial numbers of Aβ plaques and NFTs in postmortem brain examination, a state previously called pre-clinical AD [54] [48] [34], high pathology controls [26], or high…”
BackgroundHead, E., Azizeh, B. Y., Lott, I. T., Tenner, A. J., Cotman, C. W., & Cribbs, D. H. (2001) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0380 · Cited by 103 · see citing works
“In AD, SP are associated with reactive microglia, astrocytes (Carpenter et al., 1993; Maat-Schieman et al., 1994; Potter et al., 1992) and proteins of the complement system (Eikelenboom et al., 1982; Lue et al., 1996).”
BackgroundComplement-Mediated Events in Alzheimer’s Disease: Mechanisms and Potential Therapeutic Targets
Tenner, A. J. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1901068 · Cited by 99 · see citing works
“However, those data are consistent with reports of cognitively normal individuals with substantial plaque pathologic condition at autopsy (28, 29) and indicate that it is an induced response to plaque that is detrimental in AD, rather than the plaques alone.”
ResultEikelenboom, P., Rozemüller, A. J. M., & Muiswinkel, F. L. V. (1998) · Experimental Neurology · doi:10.1006/exnr.1998.6920 · Cited by 98 · see citing works
Lesions without symptoms: understanding resilience to Alzheimer disease neuropathological changes
Gómez-Isla, T., & Frosch, M. P. (2022) · Nature Reviews Neurology · doi:10.1038/s41582-022-00642-9 · Cited by 96 · see citing works
Amyloid plaque formation precedes dendritic spine loss
Bittner, T., Burgold, S., Dorostkar, M. M., Fuhrmann, M., Wegenast‐Braun, B. M., Schmidt, B., Kretzschmar, H. A., & Herms, J. W. (2012) · Acta Neuropathologica · doi:10.1007/s00401-012-1047-8 · Cited by 92 · see citing works
“For instance, plaques are associated with substantial inflammatory responses including activation of microglia and astrocytes [13, 38, 57].”
BackgroundVelagapudi, R., Aderogba, M. A., & Olajide, O. A. (2014) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2014.08.008 · Cited by 93 · see citing works
The Inflammatory Response in Alzheimer's Disease
Rogers, J. (2008) · Journal of Periodontology · doi:10.1902/jop.2008.080171 · Cited by 92 · see citing works
Self-citationNeuropathological approaches to cerebral aging and neuroplasticity
Jellinger, K. A., & Attems, J. (2013) · Dialogues in Clinical Neuroscience · doi:10.31887/dcns.2013.15.1/kjellinger · Cited by 90 · see citing works
Lee, M. Y., Lee, J.-H., Hyeon, S. J., Cho, H., Hwang, Y. J., Shin, J., McKee, A. C., Kowall, N. W., Kim, J., Stein, T. D., et al. (2020) · Aging Cell · doi:10.1111/acel.13153 · Cited by 89 · see citing works
Friend, Foe or Both? Immune Activity in Alzheimer’s Disease
Frost, G. R., Jonas, L. A., & Li, Y. (2019) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2019.00337 · Cited by 86 · see citing works
“Immune Activity in Alzheimer’s Disease Georgia R. Frost1*†, Lauren A. Jonas1,2† and Yue-Ming Li1,2 1 Chemical Biology Program, Memorial Sloan Kettering Cancer Center, Manhattan, NY, United States, 2 Pharmacology Program, Weill Cornell Graduate School of Medical Sciences, Cornell University, Ithaca, NY, United States A…”
BackgroundInfluentialChromogranin peptides in Alzheimer's disease
Lechner, T., Adlassnig, C., Humpel, C., Kaufmann, W. A., Maier, H., Kramer-Reinstadler, K., Hinterhoelzl, J., Mahata, S. K., Jellinger, K. A., & Marksteiner, J. (2003) · Experimental Gerontology · doi:10.1016/j.exger.2003.09.018 · Cited by 86 · see citing works
Differential Activation of Microglia After Experimental Spinal Cord Injury
Watanabe, T., Yamamoto, T., ABE, Y., et al. (1999) · Journal of Neurotrauma · doi:10.1089/neu.1999.16.255 · Cited by 83 · see citing works
“…infection (Gendelman and Tardieu, 1994), de-myelination (Bauer et al., 1996; Scolding et al., 1994), inflammation (Cuzner et al., 1994; Perry et al., 1993), degeneration (Lue et al., 1996; Shimoji et al., 1995), and ischemia (Gehrmann et al., 1995), microglia are known to react to such insults.”
Etiology and Pathogenesis of Late-Onset Alzheimer’s Disease
Balin, B. J., & Hudson, A. P. (2014) · Current Allergy and Asthma Reports · doi:10.1007/s11882-013-0417-1 · Cited by 79 · see citing works
Synaptic Pathology in Prefrontal Cortex is Present Only with Severe Dementia in Alzheimer Disease
Minger, S. L., Honer, W. G., Esiri, M. M., McDonald, B., Keene, J., Nicoll, J. A. R., Carter, J., Hope, T., & Francis, P. T. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.929 · Cited by 76 · see citing works
“Increasing evidence suggests that prefrontal synapses in AD are relatively intact until the later stages of the illness (24, 25).”
Chlamydia pneumoniae: An Etiologic Agent for Late-Onset Dementia
Balin, B. J., Hammond, C. J., Little, C. S., Hingley, S. T., Al-Atrache, Z., Appelt, D. M., Whittum-Hudson, J. A., & Hudson, A. P. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00302 · Cited by 77 · see citing works
“…the brains of rats elicits an inflammatory response characterized by increased production of cytokines as well as activation ofmicroglial cells (Hauss-Wegrzyniak et al., 1998); this inflammation is comparable to that currently attributed to Aβ deposition in the late-onset brain (Lue et al., 1996).”
BackgroundProinflammatory and Vasoactive Effects of Aβ in the Cerebrovasculature
Townsend, K. P., Obregon, D. F., QUADROS, A., Patel, N. S., Volmar, C., Paris, D., & MULLAN, M. J. (2002) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2002.tb04799.x · Cited by 76 · see citing works
de Vries, L. D., Huitinga, I., Kessels, H. W., Swaab, D., & Verhaagen, J. (2024) · Molecular Neurodegeneration · doi:10.1186/s13024-024-00719-7 · Cited by 78 · see citing works
Insulin-degrading Enzyme in Brain Microvessels
Morelli, L., Llovera, R. E., Mathov, I., Lue, L., Frangione, B., Ghiso, J. A., & Castaño, E. M. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m407283200 · Cited by 77 · see citing works
Self-citationNeuroinflammatory Signaling in the Pathogenesis of Alzheimer’s Disease
Uddin, M. S., Kabir, M. T., Jalouli, M., Rahman, M. A., Jeandet, P., Behl, T., Alexiou, A. T., Albadrani, G. M., Abdel‐Daim, M. M., Perveen, A., et al. (2021) · Current Neuropharmacology · doi:10.2174/1570159x19666210826130210 · Cited by 76 · see citing works
“It has also been observed that Aβ-stimulated microglia produces reactive oxygen species (ROS) [62, 63].”
BackgroundInfluentialA Perspective on Inflammation in Alzheimer's Disease
Rogers, J., & Shen, Y. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb05571.x · Cited by 74 · see citing works
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Acetylated tau in Alzheimer's disease: An instigator of synaptic dysfunction underlying memory loss
Tracy, T. E., & Gan, L. (2017) · BioEssays · doi:10.1002/bies.201600224 · Cited by 72 · see citing works
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Ibuprofen and apigenin induce apoptosis and cell cycle arrest in activated microglia
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Cuervo-Zanatta, D., Syeda, T., Sánchez-Valle, V., Irene-Fierro, M., Torres‐Aguilar, P. C., Torres-Ramos, M., Shibayama-Salas, M., Silva-Olivares, A., Noriega, L. G., Torres, N., et al. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01268-7 · Cited by 75 · see citing works
“1 3 astrocytes is disrupted, as reactive astrocytes and the released pro-inflammatory cytokines provoke neuronal damage and synapse degeneration (Lue et al. 1996; Perez-Nievas et al. 2013).”
BackgroundNeutrophils CD11b and fibroblasts PGE2 are elevated in Alzheimer’s disease
Scali, C., Prosperi, C., Bracco, L., Piccini, C., Baronti, R., Ginestroni, A., Sorbi, S., Pepeu, G., & Casamenti, F. (2002) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00346-3 · Cited by 70 · see citing works
The role of inflammatory processes in Alzheimer’s disease
Broussard, G. J., Mytar, J. O., Li, R., & Klapstein, G. J. (2012) · Inflammopharmacology · doi:10.1007/s10787-012-0130-z · Cited by 68 · see citing works
Cerebrospinal Fluid Profile of Lipid Mediators in Alzheimer’s Disease
Do, K. V., Hjorth, E., Wang, Y., Jun, B., Kautzmann, M.-A. I., Ohshima, M., Eriksdotter, M., Schultzberg, M., & Bazan, N. G. (2022) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-022-01216-5 · Cited by 65 · see citing works
- Authors
- Lue, L.-F., Brachova, L., Civin, H. W., & Rogers, J.
- Affiliations
- Banner Sun Health Research Institute (US)
- Corresponding author
- Rogers, Joseph
- ORCID
- Lue, Lih-Fen
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1996-10
- Volume
- 55
- Issue
- 10
- Pages
- 1083-1088
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W4296391647
- Cited by
- 246
- References
- 0
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 7 · 2023: 10 · 2022: 9 · 2021: 14 · 2020: 13 · 2019: 10 · 2018: 7 · 2017: 9 · 2016: 6 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 7
- FWCI
- 4.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, neuroinflammation, amyloid-beta deposition, neurofibrillary tangles, entorhinal cortex, superior frontal gyrus, synaptic loss, synaptophysin, microglial activation, MHC class II, neurodegeneration, non-demented elderly
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