APOE4 accelerates advanced-stage vascular and neurodegenerative disorder in old Alzheimer’s mice via cyclophilin A independently of amyloid-β

Abstract

he APOE4 variant of apolipoprotein E is the strongest genetic risk factor for AD 1 . One and two APOE4 alleles increase risk for AD by approximately 4-and 15-fold, respectively, compared to the more-common APOE3 gene that carries lower risk for AD 1 . Besides accelerating onset and progression of dementia, APOE4 is associated with different brain pathologies. For example, APOE4 accelerates BBB breakdown and degeneration of brain capillary pericytes 2,3 that maintain BBB integrity [4][5][6] and leads to cerebral blood flow (CBF) reduction 7,8 and dysregulation 7,9,10 . APOE4 is toxic to neurons 11 and accelerates tau-mediated neurodegeneration 12 . Additionally, APOE4 slows down amyloid-β (Aβ) clearance 13,14 and accelerates amyloid deposition [14][15][16] , which promotes development of amyloid pathology.Recent studies focused on very early stages in the Alzheimer's continuum in individuals who are cognitively unimpaired or with mild cognitive impairment (MCI) have shown that individuals bearing an APOE4 variant (APOE3/APOE4 or APOE4/APOE4) are distinguished from APOE3 homozygotes by breakdown in the BBB in the hippocampus and medial temporal lobe, regions responsible for memory encoding and cognitive functions 17 . This finding is apparent in cognitively unimpaired APOE4 carriers and more severe in those with MCI and is independent of Aβ or tau pathology measured in the cerebrospinal fluid or in brain by positron emission tomography 17 . These findings support the growing evidence suggesting that vascular dysfunction, BBB breakdown and vascular disorder contribute to early cognitive impairment and AD [17][18][19][20][21][22][23][24][25][26] . On the other hand, accumulation of Aβ in the brain has also been suggested to occur years before cognitive impairment and continues to increase with disease progression 27 . Although it has been shown that vascular dysfunction contributes to early cognitive impairment in ways that may not be exclusively related to classical AD pathology 17,19,20,26 , the respective contributions of the BBB pathway and vascular disorder versus amyloid-β pathway to advanced disease stage during progression of neurodegenerative disorder and cognitive decline in AD are still poorly understood.To address this question, here we studied vascular dysfunction, Aβ pathology, neuronal dysfunction and behavior in older APOE3 and APOE4 knock-in mice 28 alone and crossed with the 5xFAD line 29 . All mice were derived from the same litters, as previously described 30 . Mice lacking Apoe 3 and/or expressing human APOE4 develop early BBB breakdown 3,[31][32][33] and CBF dysregulation 10 . On the other hand, the 5xFAD line also develops BBB breakdown [34][35][36][37] , CBF reductions 38 and neuron and synaptic loss at a later stage 29,39 , whereas APOE3;5xFAD and APOE4;5xFAD mice (also known as E3FAD and E4FAD lines, respectively 30 ) have comparable Aβ pathology at an older age 40 . These features of the studied models allowed us to interrogate how different pathologies in APOE4 compared to APOE3 mice relat...

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…So far, very few studies have visualized the BBB integrity by using MRI in animal models of AD. Montagne et al recently showed an impaired BBB integrity by using DCE-MRI assisted with Gd-DTPA in 5×FAD and APOE4 mice [202] (Figure 2a-d) (Table 3). Dickie et al reported that DCE-MRI did not detected the difference between the TgF344 and wild-type rats at 18 months-of-age, and that increased BBB water permeability was detected by using multi-flip angle multi-echo (MFAME) water-exchange MRI in TgF344 rats compared to wild-type [203].…”

“…[81] T2* Tg SwDI mice [145] T2*w APP23 mice [144] DCE 5×FAD, APOE mice [202] MFAME-DCE TgF344 rats [203,204] T2*w,…”

Magnetic Resonance Imaging in Animal Models of Alzheimer’s Disease Amyloidosis

“…Dynamic contrast-enhanced (DCE)-MRI has been used to detect the impaired BBB integrity in the hippocampus of patients with early AD [ 244 ]. Montagne et al recently demonstrated impaired BBB integrity in 5 × FAD and APOE4 mice compared to wild-type mice by using DCE-MRI assisted with Gd-DTPA [ 141 ] ( Figure 2 a–d) ( Table 3 ). Dickie et al reported that DCE-MRI failed to detect the difference between the TgF344 rats and wild-type rats at 18 months-of-age and that the increased BBB water permeability was detected by using multi-flip angle multi-echo (MFAME) water-exchange MRI in TgF344 rats compared to wild-type rats [ 245 ].…”

“…Blue, lectin+ endothelial profiles; scale bar, 20 μm. Reproduced with permission from [ 141 ] from Springer Nature. ( e – h ) High-resolution magnetic resonance angiography (MRA).…”

From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum

“…This CBF reduction has been associated with cognitive changes in mice, including a loss of ability to sustain attention (Marshall et al, 2001). Both ApoE4 transgenic and APP/PS1 mice revealed CBF reduction prior to neuronal and synaptic dysfunctions (Guo et al, 2019;Montagne et al, 2021).…”