ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Yin, Changjun; Ackermann, Susanne; Ma, Zhe; Mohanta, Sarajo; Zhang, Chuankai; Li, Yuanfang; Nietzsche, Sándor; Westermann, Martin; Li, Peng; Hu, Desheng; Bontha, Sai Vineela; Srikakulapu, Prasad; Beer, Michael; Megens, Remco T. A.; Steffens, Sabine; Hildner, Markus; Halder, Luke D.; Eckstein, Hans‐Henning; Pelisek, Jaroslav; Herms, Jochen; Roeber, Sigrun; Arzberger, Thomas; Borodovsky, Anna; Habenicht, Livia; Binder, Christoph J.; Weber, Christian; Zipfel, Peter F.; Skerka, Christine; Habenicht, Andreas J. R.

doi:10.1038/s41591-018-0336-8

Cited by 235 publications

(235 citation statements)

References 64 publications

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“…ApoE4 carriers moreover exhibit increased phosphorylation of tau which in analogy to Ab plaques also is a hallmark for AD [71]. A recent study shows how ApoE binds to activated C1q complement factor within the classical complement cascade and acts as a checkpoint inhibitor for brain inflammation and atherosclerosis [72]. This may also possibly explain the previous observations that ApoE4 carriers are associated with a stronger inflammatory response by the microglia, a hallmark of AD, than carriers of the two other isoforms [73].…”

Section: Discussionmentioning

confidence: 90%

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

et al. 2019

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Alzheimer’s disease (AD) is strongly linked to amyloid depositions of the Aβ peptide (Aβ). The lipid‐binding protein apolipoprotein E (ApoE) has been found to interfere with Aβ amyloid formation and to exert a strong clinical impact to the pathology of AD. The APOE gene exists in three allelic isoforms represented by APOE ε2, APOE ε3, and APOE ε4. Carriers of the APOE ε4 variant display a gene dose‐dependent increased risk of developing the disease. Aβ amyloids are formed via a nucleation‐dependent mechanism where free monomers are added onto a nucleus in a template‐dependent manner. Using a combination of surface plasmon resonance and thioflavin‐T assays, we here show that ApoE can target the process of fibril elongation and that its interference effectively prevents amyloid maturation. We expose a complex equilibrium where the concentration of ApoE, Aβ monomers, and the amount of already formed Aβ fibrils will affect the relative proportion and formation rate of mature amyloids versus alternative assemblies. The result illustrates a mechanism which may affect both the clearance rate of Aβ assemblies in vivo and the population of cytotoxic Aβ assemblies.

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Section: Discussionmentioning

confidence: 90%

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

et al. 2019

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“…Our study also found that proteins involved in the immune system and neuroimmune signalling are dysregulated in the AD synapse. Recent evidence has indicated that the complement system of innate immunity, particularly complement components C1q and C3, are involved in synaptic death in mouse models both downstream of Aβ and tau pathology, and that ApoE forms a complex with activated C1q which blocks initiation of the complement cascade 24, 25, 26, 27, 42 . Our study highlights the importance of these pathways in human AD brain and shows that other proteins in this cascade including complement component C4, HLA-1, and Clusterin are all increased at the synapse in AD presenting innate immunity as an attractive area for further study and therapeutic intervention.…”

Section: Discussionmentioning

confidence: 99%

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Hesse

Hurtado

Jackson

et al. 2019

Preprint

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Highlights 42• Proteomic analysis of synapses isolated from Alzheimer's disease and control subject 43 brains identifies over 5,500 proteins in human synapses. 44• In silico analysis reveals region-specific decreases in proteins involved in synaptic 45 and mitochondrial function and increases in proteins involved in neuroimmune 46 signaling and intracellular signaling in AD. 47• The apolipoprotein E4 risk gene is associated with exacerbated changes in synaptic 48 proteins in AD. 49 50 Abstract 51Degeneration of synapses in Alzheimer's disease (AD) strongly correlates with cognitive 52 decline, and synaptic pathology contributes to disease pathophysiology. We recently 53 discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein E epsilon 4 54 (APOE4), exacerbates synapse loss and synaptic accumulation of oligomeric amyloid beta in 55 human AD brain. To begin to understand the molecular cascades involved in synapse loss in 56 AD and how this is mediated by APOE, and to generate a resource of knowledge of changes 57 in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico 58 analysis of synaptoneurosome preparations from temporal and occipital cortices of human 59 AD and control subjects with known APOE gene status. Our analysis identified over 5,500 60 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-61 associated changes in multiple molecular pathways including a decreased abundance in AD 62 of proteins important for synaptic and mitochondrial function and an increased abundance of 63 proteins involved in neuroimmune interactions and intracellular signaling. 64 65

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“…Along the same lines, subjects with at least one ApoEε4 allele display early olfactory identification and olfactory memory deficits and have a higher risk to convert to AD (Murphy et al, 2009;Calhoun-Haney and Murphy, 2005;Gilbert and Murphy, 2004;Bacon et al, 1998). ApoE suppresses inflammation through its binding to the very low density lipoprotein receptor (VLDLR) and apolipoprotein receptor 2 (ApoER2) receptors in macrophages (Baitsch et al, 2011) and by inhibiting the complement cascade (Yin et al, 2019). As macrophages influence the regeneration of the olfactory epithelium after mechanical injury or infection, it is possible that the effect of ApoE on the turnover of the olfactory epithelium (Nathan et al, 2007(Nathan et al, , 2005Hussain et al, 2013) and OSN transduction (Wetter and Murphy, 2001;Covington et al, 1999) is directly mediated by the immunogenic phenotype of macrophages.…”

Section: Olfactory Gateway Of Peripheral To Central Inflammatory Respmentioning

confidence: 99%

Olfactory dysfunction in the pathophysiological continuum of dementia

Bathini

Brai

Albèri

2019

Ageing Research Reviews

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A B S T R A C TSensory capacities like smell, taste, hearing, vision decline with aging, but increasing evidence show that sensory dysfunctions are one of the early signs diagnosing the conversion from physiological to pathological brain state. Smell loss represents the best characterized sense in clinical practice and is considered as one of the first preclinical signs of Alzheimer's and Parkinson's disease, occurring a decade or more before the onset of cognitive and motor symptoms. Despite the numerous scientific reports and the adoption in clinical practice, the etiology of sensory damage as prodromal of dementia remains largely unexplored and more studies are needed to resolve the mechanisms underlying sensory network dysfunction. Although both cognitive and sensory domains are progressively affected, loss of sensory experience in early stages plays a major role in reducing the autonomy of demented people in their daily tasks or even possibly contributing to their cognitive decline. Interestingly, the chemosensory circuitry is devoid of a blood brain barrier, representing a vulnerable port of entry for neurotoxic species that can spread to the brain. Furthermore, the exposure of the olfactory system to the external environment make it more susceptible to mechanical injury and trauma, which can cause degenerative neuroinflammation. In this review, we will summarize several findings about chemosensory impairment signing the conversion from healthy to pathological brain aging and we will try to connect those observations to the promising research linking environmental influences to sporadic dementia. The scientific body of knowledge will support the use of chemosensory diagnostics in the presymptomatic stages of AD and other biomarkers with the scope of finding treatment strategies before the onset of the disease. ⁎

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ApoE attenuates unresolvable inflammation by complex formation with activated C1q

Cited by 235 publications

References 64 publications

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Olfactory dysfunction in the pathophysiological continuum of dementia

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