Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer’s Disease

Jullienne, A.; Quan, Ryan; Szu, Jenny I.; Trinh, Michelle V.; Behringer, Erik J.; Obenaus, André

doi:10.3390/biomedicines10081967

Cited by 15 publications

(8 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… Giuliani et al (2019) reported that cortical microvessel density, as evaluated by laminin immunostaining on coronal slices, was higher in 5-month-old Tg2576 mice, compared with age-matched WT, but was lower at 27 months in Tg2576 mice. We also reported an overall increase in vascular density with age in the 3xTg-AD mouse model using vessel painting ( Jullienne et al, 2022a ). Thus, across the cortex of WT and 5xFAD mice we find a generalized increase in vascular features, which appears to be independent of genotype when both sexes are combined.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

Jullienne,

Szu,

Quan

et al. 2023

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

IntroductionThe 5xFAD mouse is a popular model of familial Alzheimer’s disease (AD) that is characterized by early beta-amyloid (Aβ) deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic perturbations over its lifespan.MethodsMale and female 5xFAD and wild type (WT) littermates underwent in vivo18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging at 4, 6, and 12 months of age to assess regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” which labels all cerebral vessels and were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals, and vessel diameter.ResultsWith increasing age, vessels on the cortical surface in both 5xFAD and WT mice showed increased vessel length, vessel and junction densities. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but collateral diameters were significantly increased only in 5xFAD mice. MCA total vessel length and junction density were decreased in 5xFAD mice compared to WT at 4 months. Analysis of 18F-FDG cortical uptake revealed significant differences between WT and 5xFAD mice spanning 4–12 months. Broadly, 5xFAD males had significantly increased 18F-FDG uptake at 12 months compared to WT mice. In most cortical regions, female 5xFAD mice had reduced 18F-FDG uptake compared to WT across their lifespan.DiscussionWhile the 5xFAD mouse exhibits AD-like cognitive deficits as early as 4 months of age that are associated with increasing Aβ deposition, we only found significant differences in cortical vascular features in males, not in females. Interestingly, 5xFAD male and female mice exhibited opposite effects in 18F-FDG uptake. The MCA supplies blood to large portions of the somatosensory cortex and portions of motor and visual cortex and increased vessel length alongside decreased collaterals which coincided with higher metabolic rates in 5xFAD mice. Thus, a potential mismatch between metabolic demand and vascular delivery of nutrients in the face of increasing Aβ deposition could contribute to the progressive cognitive deficits seen in the 5xFAD mouse model.

show abstract

Section: Discussionmentioning

confidence: 88%

“…All vascular analysis methods utilized in the current study have been previously published ( Salehi et al, 2018 ; Jullienne et al, 2022a ). Briefly, classical vessel analysis was performed using AngioTool Software ( RRID:SCR_016393 ) for measures of vessel density, length, and number of junctions ( Zudaire et al, 2011 ).…”

Section: Methodsmentioning

confidence: 99%

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

Jullienne,

Szu,

Quan

et al. 2023

Front. Aging Neurosci.

Self Cite

View full text Add to dashboard Cite

show abstract

“…Vascular dysfunction, in part due to hypertension and atherosclerosis, is an early feature of AD (Sweeney et al, 2019). Of note, there are progressive cerebrovascular abnormalities in an AD mouse model (Jullienne et al, 2022).…”

Section: Hypertension and Cardiovascular Diseasementioning

confidence: 99%

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Sharp

DeCarli

Jin

et al. 2023

Front. Aging Neurosci.

View full text Add to dashboard Cite

We postulate that myelin injury contributes to cholesterol release from myelin and cholesterol dysmetabolism which contributes to Abeta dysmetabolism, and combined with genetic and AD risk factors, leads to increased Abeta and amyloid plaques. Increased Abeta damages myelin to form a vicious injury cycle. Thus, white matter injury, cholesterol dysmetabolism and Abeta dysmetabolism interact to produce or worsen AD neuropathology. The amyloid cascade is the leading hypothesis for the cause of Alzheimer’s disease (AD). The failure of clinical trials based on this hypothesis has raised other possibilities. Even with a possible new success (Lecanemab), it is not clear whether this is a cause or a result of the disease. With the discovery in 1993 that the apolipoprotein E type 4 allele (APOE4) was the major risk factor for sporadic, late-onset AD (LOAD), there has been increasing interest in cholesterol in AD since APOE is a major cholesterol transporter. Recent studies show that cholesterol metabolism is intricately involved with Abeta (Aβ)/amyloid transport and metabolism, with cholesterol down-regulating the Aβ LRP1 transporter and upregulating the Aβ RAGE receptor, both of which would increase brain Aβ. Moreover, manipulating cholesterol transport and metabolism in rodent AD models can ameliorate pathology and cognitive deficits, or worsen them depending upon the manipulation. Though white matter (WM) injury has been noted in AD brain since Alzheimer’s initial observations, recent studies have shown abnormal white matter in every AD brain. Moreover, there is age-related WM injury in normal individuals that occurs earlier and is worse with the APOE4 genotype. Moreover, WM injury precedes formation of plaques and tangles in human Familial Alzheimer’s disease (FAD) and precedes plaque formation in rodent AD models. Restoring WM in rodent AD models improves cognition without affecting AD pathology. Thus, we postulate that the amyloid cascade, cholesterol dysmetabolism and white matter injury interact to produce and/or worsen AD pathology. We further postulate that the primary initiating event could be related to any of the three, with age a major factor for WM injury, diet and APOE4 and other genes a factor for cholesterol dysmetabolism, and FAD and other genes for Abeta dysmetabolism.

show abstract

“…Microgliosis and astrocyte activation are evident by 7 months of age. [57] Microvascular damage has been reported to precede plaque formation at 3-months [58,59]. Neurovascular uncoupling has been reported in 1-month-old transgenic mice associated with decreased NO production [60].…”

Section: Xtg Mouse Modelmentioning

confidence: 99%

Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

Fang,

Fan,

Roman

2024

J Exp Neurol

View full text Add to dashboard Cite

Alzheimer’s Disease (AD) and Alzheimer’s Disease-Related Dementia (ADRD) are the primary causes of dementia that has a devastating effect on the quality of life and is a tremendous economic burden on the healthcare system. The accumulation of extracellular beta-amyloid (Aβ) plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles (NFTs) in the brain are the hallmarks of AD. They are also thought to be the underlying cause of inflammation, neurodegeneration, brain atrophy, and cognitive impairments that accompany AD. The discovery of APP, PS1, and PS2 mutations that increase Aβ production in families with early onset familial AD led to the development of numerous transgenic rodent models of AD. These models have provided new insight into the role of Aβ in AD; however, they do not fully replicate AD pathology in patients. Familial AD patients with mutations that elevate the production of Aβ represent only a small fraction of dementia patients. In contrast, those with late-onset sporadic AD constitute the majority of cases. This observation, along with the failure of previous clinical trials targeting Aβ or Tau and the modest success of recent trials using Aβ monoclonal antibodies, has led to a reappraisal of the view that Aβ accumulation is the sole factor in the pathogenesis of AD. More recent studies have established that cerebral vascular dysfunction is one of the earliest changes seen in AD, and 67% of the candidate genes linked to AD are expressed in the cerebral vasculature. Thus, there is an increasing appreciation of the vascular contribution to AD, and the National Institute on Aging (NIA) and the Alzheimer’s Disease Foundation recently prioritized it as a focused research area. This review summarizes the strengths and limitations of the most commonly used transgenic AD animal models and current views about the contribution of Aβ accumulation versus cerebrovascular dysfunction in the pathogenesis of AD.

show abstract

Progressive Vascular Abnormalities in the Aging 3xTg-AD Mouse Model of Alzheimer’s Disease

Cited by 15 publications

References 56 publications

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

Cortical cerebrovascular and metabolic perturbations in the 5xFAD mouse model of Alzheimer’s disease

White matter injury, cholesterol dysmetabolism, and APP/Abeta dysmetabolism interact to produce Alzheimer’s disease (AD) neuropathology: A hypothesis and review

Cerebrovascular Dysfunction in Alzheimer’s Disease and Transgenic Rodent Models

Contact Info

Product

Resources

About