Optical imaging in an Alzheimer’s mouse model reveals amyloid-β-dependent vascular impairment

Abstract

Alzheimer’s disease (AD) and cerebrovascular disease are often comorbid conditions, but the relationship between amyloid-β and in vivo vascular pathophysiology is poorly understood. We utilized a multimodal, multiscale optical imaging approach, including spatial frequency domain imaging, Doppler optical coherence tomography, and confocal microscopy, to quantify AD-dependent changes in a triple transgenic mouse model (3xTg-AD) and age-matched controls. From three months of age (naïve) to 20 months (severe AD), the brain tissue concentration of total and oxy-hemoglobin (Total Hb, ctO2Hb) decreased 50 and 70%, respectively, in 3xTg-AD mice. Compared to age-matched controls, significant differences in brain hemoglobin concentrations occurred as early as eight months (Total Hb: 126 ± 5 μM versus 108 ± 4 μM; ctO2Hb: 86 ± 5 μM versus 70 ± 3 μM; for control and AD, respectively). These changes were linked to a 29% vascular volume fraction decrease and 35% vessel density reduction in the 20-month-old 3xTg-AD versus age-matched controls. Vascular reduction coincided with increased brain concentration of amyloid-β protein, vascular endothelial growth factor (VEGF), and endothelial nitric oxide synthase (eNOS) at eight and 20 months compared to the three-month baseline. Our results suggest that amyloid-β blocks the normally reparative effects of upregulated VEGF and eNOS, and may accelerate in vivo vascular pathophysiology in AD.

The neuropathology and cerebrovascular mechanisms of dementia

“…117 Recently, data from triple transgenic AD mice confirmed a 50%-70% reduction in total brain tissue Hgb concentrations between 3 and 20 months of age. 118 Moreover, this severe state of hypoxia corresponded with increased concentrations of A 1-40 and A , as well as cerebrovascular factors such as vascular endothelial growth factor and endothelial nitric oxide synthase in the brain. Yet the spatiotemporal alterations in Hgb expression and correlation to A and p-tau pathologies as well as hypoxia-inducible factor-1 /Hgb role in non-AD dementias remain unknown.…”

Differential pathlength factor informs evoked stimulus response in a mouse model of Alzheimer’s disease

“…These results of lower THb and HbO 2 in the 3xTg-AD mice are in agreement with our previous measurements using NIR wavelengths. 14,15 This likely reflects decreased blood vessel density and volume in 3xTg-AD mice 38 compared to age-matched control mice, as we have shown previously. 15 Compared to controls, μ 0 s averaged 14% higher in the 3xTg-AD mice, but the difference was not significant [ Table 1 and Fig.…”

“…Isoflurane is a strong vasodilator at higher concentrations (>1.6%), 20 but cortical vasodilatory reserve has been shown to be intact in rodents anesthetized under 1.2% isoflurane. 15,21 After inducing anesthesia, the head of each mouse was secured in a stereotaxic frame (Stoelting Co.), and body temperature was maintained at 37°C with a thermistor-controlled heating pad (CWE, Inc.). We removed the skin above the scalp and thinned the skull within a 3 mm × 3 mm region of interest (ROI) bilaterally over the hindpaw cortical sensory area with a dental drill.…”

“…14 The 3xTg-AD mice developed accelerated vascular pathology as toxic amyloid and tau proteins accumulated in the brain. 15 Others observed changes in NVC in a CAA mouse model with laser speckle imaging. 16 NVC primarily has been studied in rats with multispectral imaging, which relies on the modified Beer-Lambert law (MBLL) [Eq.…”

“…However, we demonstrated that the baseline optical properties of AD and control mice are significantly different. 14,15,19 Hence, we postulate that the use of assumed baseline optical properties may lead to errors in calculating changes in hemoglobin concentrations, especially when models of cerebrovascular disease are used. The objectives of this study are twofold: (1) to compare hemodynamic response to evoked stimuli in 3xTg-AD and control mice and (2) to compare the evoked responses in mice when using commonly assumed baseline optical properties versus directly measured optical properties in the MBLL calculation.…”