APOE4-mediated amyloid-β pathology depends on its neuronal receptor LRP1

Abstract

(GB). pathology (9). Thus, it is predicted that neuronal LRP1 deficiency also prevents apoE4-related Aβ aggregation at an early stage. One limitation of our study is that we could not analyze Aβ pathology in older mice due to a reduced survival rate at the age of 12 months, for unknown reasons. At older ages, neuronal LRP1 deficiency may accelerate Aβ deposition independently of apoE4. In this regard, suppressing LRP1 levels may not be a suitable approach as potential AD therapy because LRP1 plays a critical role in maintaining brain homeostasis (5, 10). Nonetheless, increasing apoE4 amounts in the TBS-X-soluble fraction may be an alternative therapeutic intervention for AD with APOE4. Modifying apoE4 solubility and/ or retaining more apoE4 onto the cell surface at an early stage of AD could potentially be beneficial, in addition to lowering the amount of apoE4 aggregates through treatment with specific antisense oligonucleotides (27) or antibodies (28). Taken together, our results indicate that exploring interactive roles of apoE and apoE receptors in Aβ metabolism would help us to better understand the mechanisms underlying the contribution of APOE4 to the risk of AD development and progression. Methods Study approval. The Mayo Clinic Institutional Review Board approved all protocols for human study in which experimental procedures were conducted. All subjects gave informed consent. The Mayo Clinic Institutional Animal Care and Use Committee approved

Monocyte-derived alveolar macrophage apolipoprotein E participates in pulmonary fibrosis resolution

“…While ApoE did not play a role in developing the maximal fibrosis in bleomycin-treated lung, it was indispensable to the resolution of this pathology. Mechanistically, we found that ApoE was capable of binding to type I Collagen and mediating collagen phagocytosis via the ApoE receptor, low-density lipoprotein receptor-related protein 1 (LRP1) (22). Our data reveal that a previously unappreciated role of the monocyte-derived subset of AMs may not just passively respond with phenotype change during injury, but they also actively participate in resolving fibrosis and maintaining lung homeostasis.…”

Microglia prevent beta-amyloid plaque formation in the early stage of an Alzheimer’s disease mouse model with suppression of glymphatic clearance

“…ApoE can directly bind to Aβ amino-acid residues [12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28], subsequently forming apoE/Aβ complex within neurons and extracellular space [31][32][33]. Co-deposition of apoE with Aβ is a key step for Aβ brillization and plaque formation [50,51]. Therefore, blocking apoE/Aβ interaction may be a promising strategy for improving clearance of soluble Aβ from the brain, and preventing the onset of AD.…”

Dynamics of murine brain protein synthesisin vivoidentify the hippocampus, cortex and cerebellum as highly active metabolic sites

“…Expression of a mutated form of human App precursor protein in a transgenic mouse model leads to significant App deposition in the brain, but these deposits are substantially reduced by performing the same experiment in mice with an ApoE knockout background (Berul et al, 1999, Fagan et al, 2002. ApoE4 is the single largest genetic risk factor for sporadic AD and promotes disease pathology by seeding Aβ aggregation in the brain, but recent data indicate that AD risk can be reversed by loss of the neuronal receptor Lrp1 (Tachibana et al, 2019) which was identified in our experiments as undergoing active synthesis in murine brain (average heavy/light ratio: 4.9±0.2, average emPAI value: 1.8±0.2). These data indicate that pSIVOM can provide novel insight into the biology of human ApoE isoforms through study of human ApoEs knock in mouse brain proteomics, which is central to AD pathology in human patients.…”