ApoE4 exacerbates tau pathogenesis, neuroinflammation and tau-mediated neurodegeneration, independently of amyloid-β pathology

Apolipoproteins, like Apolipoprotein E (ApoE), are proteins that bind lipids to form lipoproteins. While the lipid components of lipoproteins are hydrophobic and insoluble in water, apolipoproteins are amphipathic and are soluble in water. Thus, apolipoproteins facilitate the generation of lipoprotein particles that are water-soluble and can be carried through water-based circulation like blood and lymph. ApoE in the central nervous system (CNS) is produced by astrocytes and microglia, and is a major cholesterol carrier that supports lipid transport and injury repair in the brain.

Previous work demonstrated that polymorphic alleles of APOE-ε2, ε3 and ε4-influence amyloid-β deposition in a dose- and isoform-specific fashion (E4>E3>E2), and established that the ε4 allele of APOE is the strongest genetic risk factor for Alzheimer’s Disease (AD). However, the degree to which APOE isoforms exacerbate tau-mediated neurodegeneration has heretofore not been studied. By using mice that overexpress 1N4R human tau containing a P301S mutation, which causes a form of frontotemporal dementia, and breeding these mice to human APOE knock-in or knock-out strains, Shi et al. explored the role of APOE on tau pathology.

Shi et al. determined that ApoE4 exacerbates tau-mediated neurodegeneration, independently of amyloid-β pathology, while the lack of ApoE protects against pathology. In support, compared to ApoE3- and ApoE2-expressing mice, ApoE4-expressing mice demonstrated significantly increased volume of the lateral ventricle, concomitant with the loss of tissue in the piriform cortex, hippocampus and loss of the granule layer of the dentate gyrus. Moreover, microglia and astrocytes isolated from ApoE4-expressing mice exhibited a marked upregulation in proinflammatory genes, which contributes to neuroinflammation and neurodegeneration. Most importantly, in vitro treatment of P301S tau-expressing neurons with recombinant ApoE alone led to increased neuronal death and these effects were most prominent when neurons were treated with ApoE4. This data suggests a direct effect of ApoE4 on neurodegeneration. In sum, the authors propose that under pathological tau accumulation, ApoE, and specifically ApoE4, exacerbates neurodegeneration, whereas lack of ApoE dampens neurodegeneration. Dying neurons promote neuroinflammation, which is further amplified by ApoE4 owing to its increased innate immune reactivity, aggravating neurodegeneration further.
 


Adapted from Shi, et al. 2017. Nature. 549, 523–527. Pubmed

Shi et al. determined that ApoE4 exacerbates tau-mediated neurodegeneration, independently of amyloid-β pathology, while the lack of ApoE protects against pathology. In support, compared to ApoE3- and ApoE2-expressing mice, ApoE4-expressing mice demonstrated significantly increased volume of the lateral ventricle, concomitant with the loss of tissue in the piriform cortex, hippocampus and loss of the granule layer of the dentate gyrus. Moreover, microglia and astrocytes isolated from ApoE4-expressing mice exhibited a marked upregulation in proinflammatory genes, which contributes to neuroinflammation and neurodegeneration. Most importantly, in vitro treatment of P301S tau-expressing neurons with recombinant ApoE alone led to increased neuronal death and these effects were most prominent when neurons were treated with ApoE4. This data suggests a direct effect of ApoE4 on neurodegeneration. In sum, the authors propose that under pathological tau accumulation, ApoE, and specifically ApoE4, exacerbates neurodegeneration, whereas lack of ApoE dampens neurodegeneration. Dying neurons promote neuroinflammation, which is further amplified by ApoE4 owing to its increased innate immune reactivity, aggravating neurodegeneration further .

BioLegend offers several antibodies to detect ApoE and tau isoforms by WB, ELISA and IHC. In addition, we provide a LEGENDplex™ Human Apo Panel that can assess the relative concentration of human Apolipoproteins, including ApoE4, in serum, plasma and cell culture supernatant samples.

Example standard curve generated with the
LEGENDplex™ Human Apo Panel
(Cat. No. 740454)


Strong staining of ApoE4-containing plaques on formalin fixed paraffin embedded human Alzheimer’s brain tissue using Clone 5A9 (Cat. No. 811701) at 4 µg/mL.

 

Clone Target Recognition Applications
5A9 Human ApoE4 ELISA, IHC
5B5/ApoE4 Human ApoE4 ELISA, IHC
D6E10 Human ApoE (E2, E3 and E4) ELISA, WB, IHC, IP
E6D7 Human ApoE (E2, E3 and E4) ELISA, WB, IHC, IP
3B3C32 Mouse ApoE WB
Clone Applications
Recombinant Human Tau-352 (0N3R) WB, ELISA
Recombinant Human Tau-381 (1N3R) WB, ELISA
Recombinant Human Tau-383 (0N4R) WB, ELISA
Recombinant Human Tau-410 (2N3R) WB, ELISA
Recombinant Human Tau-412 (1N4R) WB, ELISA
Recombinant Human Tau-441 (2N4R) WB, ELISA

 

Description
LEGENDplex™ Human Apolipoprotein (Apo) Panel (11-plex) with V-bottom Plate

 



BioLegend is continually striving to improve our neuroscience offering. Take a moment to fill out this survey, and you’ll be entered into a drawing for a $100 Amazon gift card!
*Any references to promotions on this page may not be valid at this time. View our promotions page for the most up-to-date promotions.
ProductsHere
Insert Note Here
Save Close Clear
Lab Timer
Tools
Login/Register
Remember me
Forgot your password? Reset Password
Request an Account