Brain-Reactive Autoantibodies Prevalent in Human Sera Increase Intraneuronal Amyloid-β 1-42 Deposition
Authors: Nagele, Robert G. | Clifford, Peter M. | Siu, Gilbert | Levin, Eli C. | Acharya, Nimish K. | Han, Min | Kosciuk, Mary C. | Venkataraman, Venkat | Zavareh, Semah | Zarrabi, Shabnam | Kinsler, Kristin | Thaker, Nikhil G. | Nagele, Eric P. | Dash, Jacqueline | Wang, Hoau Y. | Levitas, Andrew
Article Type: Research Article
Abstract: Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β42 (Aβ42 ) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the …intraneuronal deposition of soluble Aβ42 peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ42 accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ42 peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ42 accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ42 in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases. Show more
Keywords: Alzheimer's disease, amyloid, autoantibodies, autoimmunity, blood brain barrier, neurodegenerative disease
DOI: 10.3233/JAD-2011-110098
Citation: Journal of Alzheimer's Disease, vol. 25, no. 4, pp. 605-622, 2011
A Chronic Increase in Blood-Brain Barrier Permeability Facilitates Intraneuronal Deposition of Exogenous Bloodborne Amyloid-Beta 1–42 Peptide in the Brain and Leads to Alzheimer’s Disease-R…
Authors: Acharya, Nimish K. | Grossman, Henya C. | Clifford, Peter M. | Levin, Eli C. | Light, Kenneth R. | Choi, Hana | Swanson II, Randel L. | Kosciuk, Mary C. | Venkataraman, Venkat | Libon, David J. | Matzel, Louis D. | Nagele, Robert G.
Article Type: Research Article
Abstract: Background: Increased blood-brain barrier (BBB) permeability and amyloid-β (Aβ) peptides (especially Aβ1–42 ) (Aβ42 ) have been linked to Alzheimer’s disease (AD) pathogenesis, but the nature of their involvement in AD-related neuropathological changes leading to cognitive changes remains poorly understood. Objective: To test the hypothesis that chronic extravasation of bloodborne Aβ42 peptide and brain-reactive autoantibodies and their entry into the brain parenchyma via a permeable BBB contribute to AD-related pathological changes and cognitive changes in a mouse model. Methods: The BBB was rendered chronically permeable through repeated injections of Pertussis toxin (PT), and soluble monomeric, fluorescein isothiocyanate (FITC)-labeled or unlabeled …Aβ42 was injected into the tail-vein of 10-month-old male CD1 mice at designated intervals spanning ∼3 months. Acquisition of learned behaviors and long-term retention were assessed via a battery of cognitive and behavioral tests and linked to neuropathological changes. Results: Mice injected with both PT and Aβ42 demonstrated a preferential deficit in the capacity for long-term retention and an increased susceptibility to interference in selective attention compared to mice exposed to PT or saline only. Immunohistochemical analyses revealed increased BBB permeability and entry of bloodborne Aβ42 and immunoglobulin G (IgG) into the brain parenchyma, selective neuronal binding of IgG and neuronal accumulation of Aβ42 in animals injected with both PT and Aβ42 compared to controls. Conclusion: Results highlight the potential synergistic role of BBB compromise and the influx of bloodborne Aβ42 into the brain in both the initiation and progression of neuropathologic and cognitive changes associated with AD. Show more
Keywords: Aβ42, Alzheimer’s disease, amyloid-beta peptides, amyloid plaques, autoantibodies, blood-brain barrier, dementia, immunoglobulin G
DOI: 10.3233/JAD-231028
Citation: Journal of Alzheimer's Disease, vol. 98, no. 1, pp. 163-186, 2024
Diabetes and Hypercholesterolemia Increase Blood-Brain Barrier Permeability and Brain Amyloid Deposition: Beneficial Effects of the LpPLA2 Inhibitor Darapladib
Authors: Acharya, Nimish K. | Levin, Eli C. | Clifford, Peter M. | Han, Min | Tourtellotte, Ryan | Chamberlain, Dean | Pollaro, Michael | Coretti, Nicholas J. | Kosciuk, Mary C. | Nagele, Eric P. | DeMarshall, Cassandra | Freeman, Theresa | Shi, Yi | Guan, Chenbing | Macphee, Colin H. | Wilensky, Robert L. | Nagele, Robert G.
Article Type: Research Article
Abstract: Diabetes mellitus (DM) and hypercholesterolemia (HC) have emerged as major risk factors for Alzheimer's disease, highlighting the importance of vascular health to normal brain functioning. Our previous study showed that DM and HC favor the development of advanced coronary atherosclerosis in a porcine model, and that treatment with darapladib, an inhibitor of lipoprotein-associated phospholipase A2 , blocks atherosclerosis progression and improves animal alertness and activity levels. In the present study, we examined the effects of DM and HC on the permeability of the blood-brain barrier (BBB) using immunoglobulin G (IgG) as a biomarker. DMHC increased BBB permeability and the leak …of microvascular IgG into the brain interstitium, which was bound preferentially to pyramidal neurons in the cerebral cortex. We also examined the effects of DMHC on the brain deposition of amyloid peptide (Aβ42 ), a well-known pathological feature of Alzheimer's disease. Nearly all detectable Aβ42 was contained within cortical pyramidal neurons and DMHC increased the density of Aβ42 -loaded neurons. Treatment of DMHC animals with darapladib reduced the amount of IgG-immunopositive material that leaked into the brain as well as the density of Aβ42 -containing neurons. Overall, these results suggest that a prolonged state of DMHC may have chronic deleterious effects on the functional integrity of the BBB and that, in this DMHC pig model, darapladib reduces BBB permeability. Also, the preferential binding of IgG and coincident accumulation of Aβ42 in the same neurons suggests a mechanistic link between the leak of IgG through the BBB and intraneuronal deposition of Aβ42 in the brain. Show more
Keywords: Alzheimer's disease, amyloid-β, autoantibodies, blood-brain barrier, cholesterol, darapladib, diabetes mellitus, immunoglobulin, lipoprotein-associated phospholipase-A2 (LpPLA2), microvasculature
DOI: 10.3233/JAD-122254
Citation: Journal of Alzheimer's Disease, vol. 35, no. 1, pp. 179-198, 2013