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Plaque and cerebral vessel imaging in an APPswe/PS1∆E9 trans- genic mouse (7-month-old; male). Methoxy-X04 (5 mg/kg) was injected intra- peritoneally 1 day before the imaging session for plaque imaging. Texas Red- dextran (70 kDa) was injected intravenously on the day of imaging for vessel imaging. Imaging using two-photon laser scanning microscopy was performed up to a depth of 100 μm from the exposed dura. Amyloid aggregates (blue) are deposited on the cerebral arteriole wall (cerebral amyloid angiopathy; CAA) as well as in the brain parenchyma (amyloid plaques). CAA is not observed around the veins or dura vessels. (Red, cerebral blood vessel stained with Tex- as Red-dextran; a, arteriole; d, dura vessel; v, vein; arrowheads, amyloid plaques; scale bar= 100 μm)
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In this study, we used 7-month-old male APPswe/PS1ÎE9 transgenic mice (Jackson Laboratory). One day prior to imaging, methoxy-X04 (5 mg/kg; dissolved in 10% DMSO, 45% propylene glycol, and 45% phosphate-buffered saline) was injected intraperitoneally. This probe has been used for in vivo imaging of amyloid plaques in several studies.4,5 On the day...
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... would like to share an in vivo image of cerebral amyloid angiopathy (CAA) in an Alzheimer’s disease (AD) mouse model. In AD, insoluble amyloid beta (Aβ) protein forms plaques in the parenchyma and also accumulates along the vessel walls. 1 The Aβ usually accumulates in the tunica intima and tunica media layers of the vessels. CAA in AD is attributed to the failure of Aβ clearance from the brain through perivascular drainage pathways. 2 In addition, CAA is thought to be responsi- ble for the small vessel pathology that leads to ischemic changes in the white matter in AD. Thus, observation of CAA in regards to white matter lesions or other pathophysiology is important in understanding the development of AD. However, neuro- pathological studies have typically relied on sections from brain tissues at autopsy, which hampers understanding of the dynam- ics and topographic distribution of CAA. Cutting-edge optical techniques such as multi-photon laser scanning microscopy en- able us to observe CAA in live animals in 3D. 3 In this study, we used 7-month-old male APPswe/PS1ΔE9 transgenic mice (Jackson Laboratory). One day prior to imaging, methoxy-X04 (5 mg/kg; dissolved in 10% DMSO, 45% propylene glycol, and 45% phosphate-buffered saline) was injected intraperitoneally. This probe has been used for in vivo imaging of amyloid plaques in several studies. 4,5 On the day of sur- gery, the mouse was anesthetized with ketamine and xylazine (0.12 mg/g and 0.01 mg/g, respectively), and a 2 × 2 mm crani- otomy was made over the somatosensory area leaving the dura intact. The cortex was covered with 1% agarose and a glass cov- er slip. Texas Red-dextran (70 kDa, 100 μL, 5 mg/mL) was injected via the tail vein. All procedures were approved by the KAIST Institutional Animal Care and Use Committee (IA- CUC). We used a multi-photon laser scanning microscope (LSM510, Zeiss, Germany) and a tunable near-infrared femto- second pulsed-laser (Chameleon II, Coherent, USA). Images were taken using a 20 × objective lens (NA 1.0; Carl Zeiss) with a frame rate of 0.5-1 Hz. All images were obtained using the pulsed laser at an excitation wavelength of 800 nm. We discrim- inated between arterioles and venules based on the direction of red blood cell flow and the morphology of the vessels. As shown in the Figure 1 (and supplementary movie clip 1 for z-stack image), Aβ deposits were wrapped around the vessel wall in patches. Most plaques did not form complete rings forms at this stage. Seven months is still relatively young, and older mice would have dense Aβ deposits and complete ring forms of CAA. Interestingly, CAA was not observed in either the veins or the dura vessels. 1 This finding supports the concept that CAA is formed by failure of Aβ elimination along the peri- arterial wall, but not along the peri-venous wall. 6 ...
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... Multi-transgenic mouse models with more than one pathological and cognitive changes are summarized in Table 5 ( Adalbert et al., 2009;Arancio et al., 2004;Arendash et al., 2001;Baglietto-Vargas et al., 2021;Bellucci et al., 2007;Billings et al., 2005;Borchelt et al., 1997;Borchelt et al., 1996;Bouter et al., 2013;Brautigam et al., 2012;Breyhan et al., 2009;Buskila et al., 2013;Cacciottolo et al., 2021;Caruso et al., 2013;Casas et al., 2004;Cheng-Hathaway et al., 2018;Cheng et al., 2004;Cheng et al., 2007;Chishti et al., 2001;Codita et al., 2010;Colton et al., 2008;Crouzin et al., 2013;Davis et al., 2004;Davis et al., 2006;Domnitz et al., 2005;Dudal et al., 2004;Flanigan et al., 2014;Garcia-Alloza et al., 2006;Gengler et al., 2010;Giannoni et al., 2016;Gordon et al., 2002;Gratuze et al., 2020;Grueninger et al., 2010;Hashimoto et al., 2019;Havas et al., 2011;Holcomb et al., 1998;Hong et al., 2016;Howlett et al., 2008;Howlett et al., 2004;Hsia et al., 1999;Hu et al., 2018;Hyman and Tanzi, 2019;Jackson et al., 2013;Jackson et al., 2016;Jankowsky et al., 2004;Jankowsky et al., 2005;Jankowsky et al., 2001;Jawhar et al., 2012;Jay et al., 2017;Kamphuis et al., 2012;Kang et al., 2021;Kim and Jeong, 2015;Kimura et al., 2012;Kimura and Ohno, 2009; Kno- Absent. ...
... ------ (Reaume et al., 1996) Humanize (Borchelt et al., 1997;Borchelt et al., 1996;Puoliväli et al., 2002;Wang et al., 2003) Humanize mouse Aβ region: G676R -Deficits in MWM at 6-10 months and worsen with age. (Jackson et al., 2013;Jankowsky et al., 2001;Kim and Jeong, 2015;Malm et al., 2007;Minkeviciene et al., 2008) (To be continued on the next page) Absent. ...
... Plaques emerged in cortex at 4 months, progressed to the hippocampus at 6 months, and increased in size and number with age (Jackson et al., 2013;Minkeviciene et al., 2008). There was amyloid deposition on the cerebral arteriole wall at 7 months (Kim and Jeong, 2015). Cognitive impairment measured by MWM was observed between 6 and 10 months and worsened with age. ...
Transgenic models are useful tools for studying the pathogenesis of and drug development for Alzheimer's Disease (AD). AD models are constructed usually using overexpression or knock-in of multiple pathogenic gene mutations from familial AD. Each transgenic model has its unique behavioral and pathological features. This review summarizes the research progress of transgenic mouse models, and their progress in the unique mechanism of amyloid-β oligomers, including the first transgenic mouse model built in China based on a single gene mutation (PSEN1 V97L) found in Chinese familial AD. We further summarized the preclinical findings of drugs using the models, and their future application in exploring the upstream mechanisms and multitarget drug development in AD.
... We found that both types of perivascular clearance were impaired in middle-aged Tg mice and further impaired in old age. At middle-age, CAA of the surface arteries became clear and other pathological changes, such as augmented hemodynamic response, also became apparent [23,24]. The tracer injected into parenchyma was distributed in the BM of the capillaries and penetrating arteries (Fig. 4b). ...
Cerebral amyloid angiopathy (CAA), defined as the accumulation of amyloid-beta (Aβ) on the vascular wall, is a major pathology of Alzheimer’s disease (AD) and has been thought to be caused by the failure of Aβ clearance. Although two types of perivascular clearance mechanisms, intramural periarterial drainage (IPAD) and the perivascular cerebrospinal fluid (CSF) influx, have been identified, the exact contribution of CAA on perivascular clearance is still not well understood. In this study, we investigated the effect of CAA on the structure and function of perivascular clearance systems in the APP/PS1 transgenic mouse model. To investigate the pathological changes accompanied by CAA progression, the key elements of perivascular clearance such as the perivascular basement membrane, vascular smooth muscle cells (vSMCs), and vascular pulsation were evaluated in middle-aged (7–9 months) and old-aged (19–21 months) mice using in vivo imaging and immunofluorescence staining. Changes in IPAD and perivascular CSF influx were identified by ex vivo fluorescence imaging after dextran injection into the parenchyma or cisterna magna. Amyloid deposition on the vascular wall disrupted the integrity and morphology of the arterial basement membrane. With CAA progression, vascular pulsation was augmented, and conversely, vSMC coverage was decreased. These pathological changes were more pronounced in the surface arteries with earlier amyloid accumulation than in penetrating arteries. IPAD and perivascular CSF influx were impaired in the middle-aged APP/PS1 mice and further aggravated in old age, showing severely impaired tracer influx and efflux patterns. Reduced clearance was also observed in old wild-type mice without changing the tracer distribution pattern in the influx and efflux pathway. These findings suggest that CAA is not merely a consequence of perivascular clearance impairment, but rather a contributor to this process, causing changes in arterial function and structure and increasing AD severity.
... Besides the brain parenchyma, the Aβ peptides deposit extensively in the vessel walls, which causes cerebral amyloid angiopathy (CAA) [3]. A remarkable experiment applying in vivo imaging of CAA in seven-month-old AD mice by Kim et al. (2015) demonstrated the Aβ deposits wrapped around the vessel wall in patches [4]. Of note, plaques do not form complete rings at this stage and Remarkably, typical astroglial degeneration, with a substantial reduction in the number of extending processes and independent of Aβ deposition, is prominent in the entorhinal cortex of onemonth-old and the prefrontal cortex of three-month-old homozygous triple-transgenic mice models of Alzheimer's disease (3×Tg-AD) [25]. ...
... Besides the brain parenchyma, the Aβ peptides deposit extensively in the vessel walls, which causes cerebral amyloid angiopathy (CAA) [3]. A remarkable experiment applying in vivo imaging of CAA in seven-month-old AD mice by Kim et al. (2015) demonstrated the Aβ deposits wrapped around the vessel wall in patches [4]. Of note, plaques do not form complete rings at this stage and Remarkably, typical astroglial degeneration, with a substantial reduction in the number of extending processes and independent of Aβ deposition, is prominent in the entorhinal cortex of onemonth-old and the prefrontal cortex of three-month-old homozygous triple-transgenic mice models of Alzheimer's disease (3×Tg-AD) [25]. ...
Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy metabolism, and chronic oxidative stress. Likewise, the blood-brain barrier (BBB) dysfunction is suggested to be a cause and AD consequence. Accordingly, therapeutic targeting of the compromised BBB is a promising disease-modifying approach. We utilized a homozygous triple-transgenic mouse model of AD (3×Tg-AD) to assess the effects of L-norvaline on BBB integrity. We scrutinized the perivascular astrocytes and macrophages by measuring the immunopositive profiles in relation to the presence of β-amyloid and compare the results with those found in wild-type animals. Typically, 3×Tg-AD mice display astroglia cytoskeletal atrophy, associated with the deposition of β-amyloid in the endothelia, and declining nitric oxide synthase (NOS) levels. L-norvaline escalated NOS levels, then reduced rates of BBB permeability, amyloid angiopathy, microgliosis, and astrodegeneration, which suggests AD treatment agent efficacy. Moreover, results undergird the roles of astrodegeneration and microgliosis in AD-associated BBB dysfunction and progressive cognitive impairment. L-norvaline self-evidently interferes with AD pathogenesis and presents a potent remedy for angiopathies and neurodegenerative disorders intervention.
