Bhattarai P, Gunasekaran TI, Belloy ME, Reyes-Dumeyer D, Jülich D, Tayran H, Yilmaz E, Flaherty D, Turgutalp B, Sukumar G, Alba C, McGrath EM, Hupalo DN, Bacikova D, Le Guen Y, Lantigua R, Medrano M, Rivera D, Recio P, Nuriel T, Ertekin-Taner N, Teich AF, Dickson DW, Holley S, Greicius M, Dalgard CL, Zody M, Mayeux R, Kizil C, Vardarajan BN. Rare genetic variation in fibronectin 1 (FN1) protects against APOEε4 in Alzheimer's disease. Acta Neuropathol. 2024 Apr 10;147(1):70. PubMed.
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Icahn School of Medicine at Mt. Sinai
Icahn School of Medicine at Mount Sinai
APOE4 is the strongest risk factor for Alzheimer’s disease. APOE4 homozygosity was recently identified as a distinct, highly penetrant form of AD. However, a small percentage of APOE4 homozygotes live cognitively normal lives into their 80s and beyond (Fortea et al., 2024).
The mechanisms that protect against APOE4 and other forms of AD are poorly understood, limiting our ability to develop therapeutics and lifestyle interventions that promote healthy cognitive aging in at-risk populations. Bhattarai et al. further our understanding of APOE4-resilience biology by exploring the genetic signatures of the AD-resilient population—APOE4 carriers who did not develop the disease. Identifying genetic factors protecting the highest-risk population will provide insight into the molecular mechanisms underlying risk and resilience to AD.
Intriguingly, the authors found that many variants in the APOE4-resilient population are in genes associated with the extracellular matrix (ECM). They then focus on a particular loss-of-function variant in the gene encoding the ECM protein fibronectin, finding that this variant reduces the odds ratio of developing AD by approximately 70 percent, and delays disease onset by 3.37 years in APOE4 carriers. Seeking to validate their genetic findings, Bhattarai and colleagues turned to the postmortem human brain, where they found that APOE4 carriers had significantly higher fibronectin deposition along the blood-brain barrier compared to APOE3 individuals. Interestingly, when accounting for AD status, APOE4 carriers with AD had significantly more fibronectin deposition compared to APOE4 individuals who are cognitively unaffected. Hypothesizing that fibronectin may be a driver of AD pathology, the authors found that inducing a loss-of-function mutation in fibronectin in zebrafish had a protective effect on amyloid toxicity, specifically via decreased gliosis, increased microglial activity, and enhanced gliovascular remodeling. In summary, the work presented by Bhattarai et al. suggests that fibronectin is linked to AD progression in APOE4 carriers, thus highlighting the therapeutic potential of targeting this protein.
The results presented here are particularly exciting given what is already known about the role of ECM dysregulation in AD. Studies show that the deposition of several ECM components, including fibronectin, increases with AD, and that fibronectin deposition in the postmortem human brain has a significant positive correlation with amyloid pathology (Bogdan et al., 2022; Lepelletier et al., 2017; Végh et al., 2014). Furthermore, fibronectin directly binds to amyloid and induces amyloid accumulation along the vasculature when injected into mice (Howe et al., 2018). While previous literature strongly supports a link between the ECM and AD, Bhattarai and colleagues uniquely introduce APOE4 to this discussion and highlight potential protective variants.
From this work, several important questions emerge. Research should aim to characterize the mechanism through which APOE4 mediates an increase in fibronectin deposition and its subsequent contribution to the development of AD pathology in human brain tissue. Additionally, further studies are needed to dissect the molecular mechanism underlying the protective effect of this fibronectin variant in the APOE4 population. Overall, it is clear from this study that ECM dysregulation is emerging as a potential driver of APOE4-driven AD progression, and this field of study will likely expand in the future.
References:
Fortea J, Pegueroles J, Alcolea D, Belbin O, Dols-Icardo O, Vaqué-Alcázar L, Videla L, Gispert JD, Suárez-Calvet M, Johnson SC, Sperling R, Bejanin A, Lleó A, Montal V. APOE4 homozygozity represents a distinct genetic form of Alzheimer's disease. Nat Med. 2024 May;30(5):1284-1291. Epub 2024 May 6 PubMed. Correction.
Bogdan S, Puścion-Jakubik A, Klimiuk K, Socha K, Kochanowicz J, Gorodkiewicz E. The Concentration of Fibronectin and MMP-1 in Patients with Alzheimer's Disease in Relation to the Selected Antioxidant Elements and Eating Habits. J Clin Med. 2022 Oct 27;11(21) PubMed.
Howe MD, Atadja LA, Furr JW, Maniskas ME, Zhu L, McCullough LD, Urayama A. Fibronectin induces the perivascular deposition of cerebrospinal fluid-derived amyloid-β in aging and after stroke. Neurobiol Aging. 2018 Dec;72:1-13. Epub 2018 Aug 9 PubMed.
Lepelletier FX, Mann DM, Robinson AC, Pinteaux E, Boutin H. Early changes in extracellular matrix in Alzheimer's disease. Neuropathol Appl Neurobiol. 2015 Nov 6; PubMed.
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View all comments by Braxton SchuldtUniversity of Arkansas for Medical Sciences
TGFꞵ1 is well-established as a contributor to cerebral amyloid angiopathy (CAA) (Wyss-Coray et al., 1997), and one of the earliest actions noted for TGFꞵ was induction of fibronectin expression (Ignotz and Massagué, 1986). It seems quite likely that this explains the TGFꞵ effect on CAA. Perhaps this relationship links to ApoE through its receptors, which generally suppress TGFꞵ actions. Cells deficient in ApoER2 show a dramatically exaggerated induction of fibronectin in response to TGFꞵ (Komaravolu et al., 2019), and deficiencies in LRP1 (Boucher et al., 2007) or VLDLR (Ma et al., 2021) are similarly permissive for vascular fibrosis. TGFꞵ1 (Huang et al., 2003) and -2 (Muratoglu et al., 2011) are both ligands for LRP1; indeed, LRP1 is also known as “TGFβ receptor V.”
A loss-of-function phenotype for ApoE4 at one or more of these receptors is perhaps the simplest explanation. But there are considerable data indicating that the relationship of APOE ε4 genotype to AD risk is mediated by a gain of (toxic) function. Joachim Herz and colleagues have emphasized the tendency of ApoE4 to “distract” its receptors within the cell’s interior, reducing the levels of functional receptor on the cell surface (Chen et al., 2010). Like the complicated impact of mutations on presenilin/γ-secretase, this is a loss masquerading as a gain; it seems to be a plausible explanation for the apparent ability of ApoE4 to suppress its active receptors and thus promote TGFꞵ actions on fibrosis.
References:
Wyss-Coray T, Masliah E, Mallory M, McConlogue L, Johnson-Wood K, Lin C, Mucke L. Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease. Nature. 1997 Oct 9;389(6651):603-6. PubMed.
Ignotz RA, Massagué J. Transforming growth factor-beta stimulates the expression of fibronectin and collagen and their incorporation into the extracellular matrix. J Biol Chem. 1986 Mar 25;261(9):4337-45. PubMed.
Komaravolu RK, Waltmann MD, Konaniah E, Jaeschke A, Hui DY. ApoER2 (Apolipoprotein E Receptor-2) Deficiency Accelerates Smooth Muscle Cell Senescence via Cytokinesis Impairment and Promotes Fibrotic Neointima After Vascular Injury. Arterioscler Thromb Vasc Biol. 2019 Oct;39(10):2132-2144. Epub 2019 Aug 15 PubMed.
Boucher P, Li WP, Matz RL, Takayama Y, Auwerx J, Anderson RG, Herz J. LRP1 functions as an atheroprotective integrator of TGFbeta and PDFG signals in the vascular wall: implications for Marfan syndrome. PLoS One. 2007 May 16;2(5):e448. PubMed.
Ma X, Takahashi Y, Wu W, Chen J, Dehdarani M, Liang W, Shin YH, Benyajati S, Ma JX. Soluble very low-density lipoprotein receptor (sVLDLR) inhibits fibrosis in neovascular age-related macular degeneration. FASEB J. 2021 Dec;35(12):e22058. PubMed.
Huang SS, Ling TY, Tseng WF, Huang YH, Tang FM, Leal SM, Huang JS. Cellular growth inhibition by IGFBP-3 and TGF-beta1 requires LRP-1. FASEB J. 2003 Nov;17(14):2068-81. PubMed.
Muratoglu SC, Belgrave S, Lillis AP, Migliorini M, Robinson S, Smith E, Zhang L, Strickland DK. Macrophage LRP1 suppresses neo-intima formation during vascular remodeling by modulating the TGF-β signaling pathway. PLoS One. 2011;6(12):e28846. Epub 2011 Dec 9 PubMed.
Chen Y, Durakoglugil MS, Xian X, Herz J. ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling. Proc Natl Acad Sci U S A. 2010 Jun 29;107(26):12011-6. Epub 2010 Jun 14 PubMed.
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