Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Aß in human AßPP transgenic mice

Davis, James Earl; Xu, Feng; Miao, Jianting; Previti, Mary Lou; Romanov, Galina; Ziegler, Kelly; Nostrand, William E. Van

doi:10.1016/j.neurobiolaging.2005.05.031

Cited by 53 publications

(47 citation statements)

References 38 publications

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“…Although no differences were found in the amounts of A␤ in nondissected forebrain hemispheres, differences may exist in A␤ levels in specific regions, reflecting the shift from microvascular to parenchymal amyloid. ELISA analysis showed no human A␤ peptide in plasma samples of any of the Tg-SwDI mice regardless of APOE genotype (data not shown), consistent with our previous studies indicating ineffective efflux of CNS Dutch/Iowa CAA mutant A␤ into the circulation (Davis et al, , 2006Deane et al, 2004). Together, these findings indicate that the type of ApoE protein expressed had no significant quantitative effect on the total accumulation of CNS A␤ peptides in Tg-SwDI mice.…”

Section: Human Apoe Promotes Fibrillar Amyloid Plaque Deposition In Tsupporting

confidence: 90%

“…The finding that Tg-SwDI mice accumulate extensive cerebral microvascular A␤, despite low levels of transgene-directed human A␤PP expression, appears to primarily result from ineffective clearance of Dutch/Iowa mutant A␤ from brain across the blood-brain barrier into the circulation (Davis et al, , 2006Deane et al, 2004). In Tg-SwDI mice, cerebral microvascular amyloid deposition is intimately linked with a robust neuroinflammatory response, highlighted by localized strong microglial activation and deficits in spatial learning and memory (Miao et al, 2005b;Fan et al, 2007;Xu et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Vitek²,

Colton³

et al. 2008

J. Neurosci.

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Human apolipoprotein (ApoE) genotype influences the development of Alzheimer's disease and cerebral amyloid angiopathy (CAA). Specific mutations within the amyloid-␤ protein (A␤) peptide have been identified that cause familial forms of CAA. However, the effect of APOE genotype on accumulation of CAA mutant A␤ in brain is not well understood. In the present study, we determined how human ApoE3 or ApoE4 influence cerebral A␤ accumulation in transgenic mice (Tg-SwDI) that accumulate human Dutch/Iowa (E22Q/D23N) CAA mutant A␤ in brain, primarily in the form of fibrillar cerebral microvascular amyloid. Using Tg-SwDI mice bred onto a human APOE3/3 or human APOE4/4 background, we found that both human ApoE3 and ApoE4 proteins led to a strong reduction in the amount of cerebral microvascular amyloid with an unexpected concomitant appearance of extensive fibrillar parenchymal plaque amyloid. There was strong colocalization of all ApoE proteins with fibrillar amyloid deposits in the mice. In Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice, there was no change in the levels of total A␤ 40 and A␤ 42 or in the amounts of soluble and insoluble A␤ in brain compared with Tg-SwDI mice on the endogenous mouse APOE background. The shift from primarily cerebral microvascular amyloid to parenchymal plaque amyloid in Tg-SwDI/hAPOE3/3 and Tg-SwDI/hAPOE4/4 mice resulted in a parallel shift in the association of activated microglia. These findings indicate that human ApoE has a strong influence on the spatial development of human Dutch/Iowa CAA mutant amyloid accumulation in mouse brain and that microglial activation is in response to the spatial accumulation of fibrillar amyloid.

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Section: Human Apoe Promotes Fibrillar Amyloid Plaque Deposition In Tsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Vitek²,

Colton³

et al. 2008

J. Neurosci.

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“…Winkler et al showed that accumulation of Aβ is sufficient to give rise to recurrent hemorrhagic stroke in APP23 mice (89). Similar findings have been reported for other transgenic mouse models overexpressing human APP harboring various mutations, including Tg2576, PDAPP (76), TgSwDI (90), and APPDutch (77), which develop spontaneous hemorrhage in association with Aβ-laden vessels. Interestingly, the loss of ApoE in Tg2576 and PDAPP mice completely prevented CAA and hemorrhage, indicating that ApoE facilitates CAA and CAA-associated hemorrhage (76).…”

Section: Discussionsupporting

confidence: 53%

[P1–183]: Loss of Clusterin Shifts Amyloid Deposition to the Cerebrovasculature via Disruption of Perivascular Drainage Pathways

Wojtas

Kang

et al. 2017

Alzheimer's & Dementia

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Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) peptide deposition in brain parenchyma as plaques and in cerebral blood vessels as cerebral amyloid angiopathy (CAA). CAA deposition leads to several clinical complications, including intracerebral hemorrhage. The underlying molecular mechanisms that regulate plaque and CAA deposition in the vast majority of sporadic AD patients remain unclear. The clusterin (CLU) gene is genetically associated with AD and CLU has been shown to alter aggregation, toxicity, and bloodbrain barrier transport of Aβ, suggesting it might play a key role in regulating the balance between Aβ deposition and clearance in both brain and blood vessels. Here, we investigated the effect of CLU on Aβ pathology using the amyloid precursor protein/presenilin 1 (APP/PS1) mouse model of AD amyloidosis on a Clu +/+ or Clu −/− background. We found a marked decrease in plaque deposition in the brain parenchyma but an equally striking increase in CAA within the cerebrovasculature of APP/PS1;Clu −/− mice. Surprisingly, despite the several-fold increase in CAA levels, APP/PS1;Clu −/− mice had significantly less hemorrhage and inflammation. Mice lacking CLU had impaired clearance of Aβ in vivo and exogenously added CLU significantly prevented Aβ binding to isolated vessels ex vivo. These findings suggest that in the absence of CLU, Aβ clearance shifts to perivascular drainage pathways, resulting in fewer parenchymal plaques but more CAA because of loss of CLU chaperone activity, complicating the potential therapeutic targeting of CLU for AD.

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“…It was discovered in a guinea pig model of the Dutch mutation that Aβ40 accumulates around the blood vessels and in the brain due to a reduced clearance from the cerebrospinal fluid and impaired transport over the blood brain barrier because of the lower affinity for central nervous system efflux transporters (Monro et al, 2002). Impaired clearance of Aβ was also shown in a mouse model with the Dutch and Iowa mutation: no detectable plasma Aβ but abundant Aβ deposits were present in cerebral vasculature (Davis et al, 2006). The double mutated Aβ shows a significant lower affinity to the low-density lipoprotein receptor-related protein 1 (LRP1), which is implicated in Aβ clearance, in comparison to wild-type Aβ40 (Deane et al, 2004).…”

Section: Aβ Isoforms In Hchwa-d Vasculaturementioning

confidence: 99%

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

Kamp

Moursel²,

Haan³

et al. 2014

Reviews in the Neurosciences

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Deficient cerebral clearance of vasculotropic mutant Dutch/Iowa Double Aß in human AßPP transgenic mice

Cited by 53 publications

References 38 publications

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

Human Apolipoprotein E Redistributes Fibrillar Amyloid Deposition in Tg-SwDI Mice

[P1–183]: Loss of Clusterin Shifts Amyloid Deposition to the Cerebrovasculature via Disruption of Perivascular Drainage Pathways

Amyloid β in hereditary cerebral hemorrhage with amyloidosis-Dutch type

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