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Microvascular Ultrastructural Changes Precede Cognitive Impairment in the Murine Appswe/Ps1de9 Model of Alzheimer’S Disease

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Microvascular Ultrastructural Changes Precede Cognitive Impairment in the Murine Appswe/Ps1de9 Model of Alzheimer’S Disease Angiogenesis DOI 10.1007/s10456-017-9568-3 ORIGINAL PAPER Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer’s disease 1 1 2 3 Patricia Kelly • Paul Denver • Simon C. Satchell • Maximilian Ackermann • 3 1 Moritz A. Konerding • Christopher A. Mitchell Received: 15 February 2017 / Accepted: 18 July 2017 Ó The Author(s) 2017. This article is an open access publication Abstract Cerebral and systemic organ microvascular number (p = 0.0002) and an increase in the number of pathologies coexist with human Alzheimer’s disease (AD) splenic microvascular pillars (p = 0.0231), in the absence neuropathology. In this study, we hypothesised that both of changes in either splenic microvascular density cerebral and systemic microvascular pathologies exist in 4- (p = 0.3746) or glomerular ultrastructure. The highly sig- to 5-month-old male APPswe/PS1dE9 (APP/PS1) trans- nificant reduction in uACR in APP/PS1 mice compared to genic mice prior to the onset of cognitive impairment. To wild-type (p = 0.0079) is consistent with glomerular assess this we examined recognition memory in both wild- microvascular dysfunction. These findings highlight early type and APP/PS1 mice using the object recognition task microvascular pathologies in 4- to 5-month-old APP/PS1 (ORT; n = 11 per group) and counted thioflavin-S-positive transgenic mice and may indicate an amenable target for plaques in brain (n = 6 per group). Vascular casts of brain, pharmacological intervention in AD. liver, spleen and kidneys were examined using scanning electron microscopy (n = 6 per group), and the urinary Keywords Alzheimer’s disease Á APP/PS1 mice Á albumin-to-creatinine ratio (uACR; n = 5 per group) was Microvascular corrosion casting Á Scanning electron measured as an index of glomerular permeability. Murine microscopy recognition memory was intact, as demonstrated by a sig- nificant preference for the novel object in the ORT para- digm. Brain sections of wild-type mice were devoid of Introduction thioflavin-S positivity, whereas age-matched APP/PS1 mice had an average of 0.88 ± 0.22 thioflavin-S-positive plaques Dementia is characterised by heterogeneous pathologies in the cortex, 0.42 ± 0.17 plaques in the dentate gyrus and associated with neurodegenerative lesions that progres- 0.30 ± 0.07 plaques in the cornus ammonis 1 region. The sively affect multiple cognitive domains and irreversibly profiles of casted cerebral capillaries of wild-type mice were impair the ability to conduct the tasks required for inde- smooth and regular in contrast to those of APP/PS1 mice pendent living [1]. Recent global estimates indicate that 46 which demonstrate characteristic (0.5–4.6 lm) ‘tags’. APP/ million individuals have dementia and with 10 million new PS1 mice also had a significantly reduced hepatic vessel cases of dementia occurring each year, it is expected that by the year 2018 the global cost of dementia will exceed 1 trillion dollars [2]. AD is the most common form of & Christopher A. Mitchell dementia, which accounts for 60–80% of all dementia [email protected] cases in the general population [2]. As the insidious 1 School of Biomedical Sciences, University of Ulster, pathological pathways to neurodegeneration remain elusive Coleraine, Northern Ireland, UK and the clinically used neurotransmitter-based therapies are 2 Dorothy Hodgkin Building, University of Bristol, Bristol, UK ineffective in altering disease course, it is expected that by the year 2050 there will be 106.8 million individuals with 3 Institute of Functional and Clinical Anatomy, University Medical Centre, Johannes Gutenberg-University Mainz, AD worldwide [3–6], highlighting the urgent need to Mainz, Germany identify causative pathology. 123 Angiogenesis The proteinaceous accumulations characteristic of AD age, which precedes the onset of amyloid plaques that includes parenchymal amyloid plaques and intraneuronal accumulate in the brain of Tg2576 mice from 11 to tau which were first formally described by Dr. Aloysius 13 months of age [21]. APP23 transgenic mice carrying the ‘Alois’ Alzheimer in 1906 following a post-mortem APP751 isoform with a double Swedish mutation [22] examination of 51-year-old Auguste Deter, who presented show multiple areas of vessel elimination in the cortex at with ante-mortem ‘delirium’ [7]. Dr. Alzheimer observed 4–5 months of age, which is prior to the onset of amyloid concomitant cerebrovascular abnormalities that included plaques at 6 months of age [23]. The aforementioned study atherosclerotic changes to large cerebral vessels, a com- used the microvascular corrosion casting technique to plete absence of infiltrating vessels and an excessive pro- recreate the three-dimensional structure of cerebral vessels liferation of the endothelium [7]. Cerebrovascular lesions using a polymerising resin solution followed by a scanning such as infarctions, lacunas and small vessel disease are electron microscopic examination of the vascular ultra- concomitant with AD neuropathology, which along with structure [23, 24]. Interestingly, an additional study of amyloid plaques and neurofibrillary tangles (NFTs) addi- APP23 mice that examined cerebral hemodynamics using tively lower the threshold for cognitive impairment [8–13]. magnetic resonance angiography prior to microvascular Clinicopathological findings show that a similar magnitude corrosion casting showed that areas of flow voids on the of cognitive dysfunction can be elicited by lower cerebral angiograms occupied the same brain regions as the vas- densities of amyloid plaques and NFTs coinciding with cular structural deformations in the resin cerebral vascular cerebrovascular lesions compared to a higher cerebral casts that were examined by scanning electron microscopy burden of amyloid plaques and NFTs alone [12, 14]. An (SEM; [25]). ante-mortem aggregation of the vascular-based risk factors In the present study, we use the microvascular corrosion for AD that include type-2 diabetes mellitus (T2DM), casting technique with SEM to recreate and examine the hypertension, hypercholesterolemia and obesity is associ- fine structure of small calibre vessels of the APPswe/ ated with an increased prevalence of cerebrovascular PS1dE9 (APP/PS1) mouse model of AD. APP/PS1 mice lesions at post-mortem [15]. carry the ‘‘Swedish mutation’’ (APP695 isoform) in addi- Pathological alterations to the integrity of the cere- tion to an exon-9 deleted variant of presenilin-1 (PS1) brovasculature may critically alter the function of the within independent vectors, which results in over-expres- neurovascular unit (NVU) and cause neuronal injury via an sion of these proteins primarily in the brain and heart impairment of cerebral perfusion, an unrestricted brain [26, 27]. APP/PS1 mice are reported to progressively entry of circulatory compounds, reduced cerebral amyloid accumulate parenchymal amyloid plaques by 4–5 months clearance and vascular and parenchymal accumulations of [28], develop cerebral amyloid angiopathy (CAA) from cerebrotoxins [13, 16, 17]. Quantitative analysis of the 6 months [28] and exhibit cognitive deficits in behavioural blood-to-brain transfer of a gadolinium contrast agent in tasks from 7 months of age [29, 30]. Accordingly, we have human participants using a high-resolution magnetic reso- examined both the cerebral and systemic vascular ultra- nance imaging (MRI) protocol showed an age-dependent structure of young 4- to 5-month-old male APP/PS1 mice and region-specific disruption of the blood–brain barrier at the age when cerebral amyloid plaques begin to accu- (BBB) in the hippocampus, a brain region critical for mulate, prior to development of both CAA and cognitive learning and memory [18]. Interestingly, the aforemen- deficits. We sought to determine whether disturbances of tioned study showed that hippocampal BBB disruption was microvascular structure and function are a systemic phe- greater in individuals with mild cognitive impairment and nomenon (rather than being CNS specific) in the APP/PS1 independent of hippocampal atrophy, demonstrating an mouse by examining organs previously shown by I125-la- early role for BBB dysfunction in the pathogenesis of AD belling studies to be associated with the metabolism of b- [18]. A recent comprehensive data-driven analysis of over amyloid, namely kidney, spleen and liver. Accordingly, we 7700 multiple-modality brain images, plasma and cere- assessed urinary albumin-to-creatinine ratios (uACR) as a brospinal fluid biomarkers from 1171 human subjects from measure of glomerular microvascular function in young 4- the Alzheimer’s Disease Neuroimaging Initiative (ADNI) to 5-month-old APP/PS1 mice. Measuring renal dysfunc- proposed that vascular dysfunction precedes amyloid pla- tion in AD is receiving attention as a potential clinical que deposition in the pathological cascade of AD [19]. marker, with a cross-sectional study of individuals with AD The findings of animal studies also support the proposal identifying a high proportion with altered kidney function that pathological changes to the vasculature are an early [33]. Furthermore, a longitudinal study showed that men event in the pathogenesis of AD. The Tg2576 transgenic [75 years of age with elevated uACR are more likely to murine AD model harbouring the amyloid precursor pro- show cognitive decline over a 6-year period [34]. In tein (APP) 695 isoform with the double Swedish mutation addition, we have shown that 9-month-old male APP/PS1 [20] exhibits cerebral hypoperfusion from 2 to 3 months
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