Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Abstract

Substantial evidence from epidemiological, pathological, and clinical reports suggests that vascular factors are critical in the pathogenesis of Alzheimer's disease (AD), and changes in blood flow are currently the most reliable indicators of the disease. We previously reported that older APP23 transgenic (tg) mice have significant blood flow alterations correlated with structural modifications of blood vessels. For the present study, our objective was to analyze the age-dependent morphological and architectural changes of the cerebral vasculature of APP23 tg mice. To visualize the 3D arrangement of the entire brain vasculature, we used vascular corrosion casts. Already at young ages, when typically parenchymal amyloid plaques are not yet present, APP23 tg mice had significant alterations, particularly of the microvasculature, often accompanied by small deposits attached to the vessels. In older animals, vasculature abruptly ended at amyloid plaques, resulting in holes. Often, small deposits were sitting near or at the end of truncated vessels. Between such holes, the surrounding vascular array appeared more dense and showed features typical for angiogenesis. We propose that small amyloid aggregates associated with the microvasculature lead to morphological and architectural alterations of the vasculature, resulting in altered local blood flow. The characteristic early onset of vascular alterations suggests that imaging blood flow and/or vasculature architecture could be used as a tool for early diagnosis of the disease and to monitor therapies. amyloid precursor protein ͉ cerebral blood flow ͉ scanning electron microscopy ͉ vascular corrosion casting T he typical clinical picture of Alzheimer's disease (AD) includes a progressive decline of memory function, often accompanied by other clinical signs such as agitation, aggression, sleep disturbances, and social withdrawal. Nonetheless, brain autopsy is needed to positively confirm the diagnosis (1). A high density of neuritic plaques, neurofibrillary tangles, and vascular amyloid (A␤) is a characteristic neuropathological marker of AD (2, 3). Plaques and tangles in the neuropil may affect neuronal function and also contribute to the neuronal damage; however, it is unclear whether their incidence correlates with the clinical signs and symptoms of cognitive impairment characteristic of the disease (4). Evidence suggests that cerebrovascular pathologies, such as structural alterations (5), atherosclerotic lesions (6), and impaired hemodynamic responses (7), are early features of AD (for review, see ref. 8). Reduced blood flow has been reported as one of the most consistent physiological deficits in AD (9, 10); however, it remains unclear whether the reduced cerebral blood flow is a response to neuronal damage or a factor initiating the characteristic neuropathology. In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-depende...

Nogo-A regulates vascular network architecture in the postnatal brain

“…Larger blood vessels showed oval imprints on the cast surface that are due to endothelial cell nuclei (Supplementary Figure S1(c)) which are also observed in vascular corrosion casts of adult mice thereby demonstrating the perfect molding of the vascular lumen. 29 The fine capillary network was well visible and devoid of vessel interruptions in these P10 brain cortices (Supplementary Figure S1(d)). All these morphological features were very similar to the characteristics of the normal cerebral vasculature in adult mice.…”

“…17,29 To investigate whether vascular corrosion casting could be applied to visualize the 3D vasculature of mice during postnatal brain development -a stage where brain angiogenesis and vascular remodeling are highly dynamic 3,4,7,9 -we perfused P10 WT mice with the polyurethane resin PU4ii (see Methods section) that was used in the above-described studies. Light microscopy and SEM of brain tissue samples from resinperfused P10 WT mice revealed a dense vascular network in the superficial cortex with well-defined vessel structures of all sizes (Supplementary Figure S1(a) to (d)).…”

Pathogenic Angiogenic Mechanisms in Alzheimer's Disease

“…The vascular plexus undergoes remodelling, that is triggered by the angiopoietin-1 (Ang-1), into a hierarchically structured mature vascular system established through endothelial cell sprouting, trimming differentiation and pericyte recruitment (normal angiogenesis) [48]. In contrast to these events in AD, it is observed that, a downstream cell signalling molecule to VEGF, angiopoietin-2 (Ang-2), destabilizes the vessel wall of mature vessels [32,[49][50][51]. The quiescent endothelial cells become sensitive to VEGF (and other angiogenic factors), proliferate indiscriminately, migrate to form new vessels that are not able to mature and eventually lead to the establishment of a leaky network of blood vessels [32].…”

“…A study using three-dimensional architectural analysis [51], revealed significant changes to be accelerated only in the amyloid positive vessels [64]. Interestingly, brain homogenates taken from Aβ-overexpressing AD model mice, demonstrated an increase in the formation of new vessels in an in vivo angiogenesis assay [52].…”

“…In vivo studies, using various APP mutant AD mouse models that have an overproduction of Aβ, show modifications in brain vasculature compared to the wild-type animals [12,25]. APP23 AD model mice exhibit significant blood flow alterations correlated with structural modifications of blood vessels [51].…”