Building in vitro models of the brain to understand the role of<i>APOE</i>in Alzheimer’s disease

Pinals, Rebecca L.; Tsai, Li‐Huei

doi:10.26508/lsa.202201542

Cited by 2 publications

(1 citation statement)

References 178 publications

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“…There is extensive data that APOE and CLU interaction with AA amyloid deposits alters the local cellular response, and influence amyloid deposition itself [86][87][88]113,114 Because of their genetic association with AD, they are also considered therapeutic targets, though it has been challenging to develop therapeutic approaches that modulate APOE or CLU and show robust preclinical disease modifying impacts 115 . We have not yet explored studies in knockout mice, however, overexpression studies suggest that Mdk and PTN, like APOE and CLU, can increase amyloid deposition and both also increase CAA.…”

Section: Discussionmentioning

confidence: 99%

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Levites,

Dammer,

Ran

et al. 2023

Preprint

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We report a highly significant correlation between human Alzheimer’s disease (AD) brain proteome changes and those in CRND8 APP695NL/F transgenic mice. Comparing protein changes observed in the CRND8 mice with co-expression networks derived from human Alzheimer’s disease (AD), reveals both conserved and divergent module changes. Many proteins in the most highly conserved module (M42, matrisome) accumulate in plaques, cerebrovascular amyloid (CAA), dystrophic neuronal processes, or a combination thereof. Overexpression of two M42 proteins, midkine (Mdk) and pleiotrophin (PTN), in CRND8 mice brains leads to increased accumulation of Aβ in plaques and in blood vessels; further, recombinant MDK and PTN enhance Aβ aggregation into amyloid structures. Multiple M42 proteins bind to fibrillar Aβ42 and a non-human amyloid fibrilin vitro. Supporting this binding data, MDK and PTN co-accumulate with transthyretin (TTR) amyloid in the heart. Notably, our findings establish that proteomic changes in modules observed in human AD brains define an Aβ amyloid “responsome” that is well conserved from mouse models to humans. Further, distinct amyloid structures appear to serve as scaffolds, facilitating the co-accumulation of proteins with signaling functions, and this co-accumulation may contribute to downstream pathological sequalae. Overall, this contextualized understanding of proteomic changes and their interplay with amyloid deposition provides valuable insights into the complexity of AD pathogenesis and potential biomarkers and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Levites,

Dammer,

Ran

et al. 2023

Preprint

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Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition

Connolly,

Margaria,

Di Biase

et al. 2023

Cells

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Tightly regulated and highly adaptive lipid metabolic and transport pathways are critical to maintaining brain cellular lipid homeostasis and responding to lipid and inflammatory stress to preserve brain function and health. Deficits in the lipid handling genes APOE and GBA1 are the most significant genetic risk factors for Lewy body dementia and related dementia syndromes. Parkinson’s disease patients who carry both APOE4 and GBA1 variants have accelerated cognitive decline compared to single variant carriers. To investigate functional interactions between brain ApoE and GBA1, in vivo GBA1 inhibition was tested in WT versus ApoE-deficient mice. The experiments demonstrated glycolipid stress caused by GBA1 inhibition in WT mice induced ApoE expression in several brain regions associated with movement and dementia disorders. The absence of ApoE in ApoE-KO mice amplified complement C1q elevations, reactive microgliosis and astrocytosis after glycolipid stress. Mechanistically, GBA1 inhibition triggered increases in cell surface and intracellular lipid transporters ABCA1 and NPC1, respectively. Interestingly, the absence of NPC1 in mice also triggered elevations of brain ApoE levels. These new data show that brain ApoE, GBA1 and NPC1 functions are interconnected in vivo, and that the removal or reduction of ApoE would likely be detrimental to brain function. These results provide important insights into brain ApoE adaptive responses to increased lipid loads.

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Building in vitro models of the brain to understand the role ofAPOEin Alzheimer’s disease

Cited by 2 publications

References 178 publications

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Aβ Amyloid Scaffolds the Accumulation of Matrisome and Additional Proteins in Alzheimer’s Disease

Loss of Lipid Carrier ApoE Exacerbates Brain Glial and Inflammatory Responses after Lysosomal GBA1 Inhibition

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