Reduced brain tissue perfusion in TGF-β1 transgenic mice showing Alzheimer's disease-like cerebrovascular abnormalities
Introduction
Epidemiological findings showing that cardiovascular diseases and dementia share certain risk factors (Skoog et al., 1999) have reemphasized the relevance of cerebrovascular factors in neurodegenerative diseases. Moreover, cerebrovascular alterations have been shown to precipitate the earliest stages of Alzheimer's disease (AD) (Esiri et al., 1999) and to aggravate cognitive impairments (Zekry et al., 2002). Cerebrovascular abnormalities or angiopathy, including thickening of the microvascular basement membrane, vascular amyloid deposition, and microvascular degeneration, are frequently observed in AD (Vinters et al., 1996) and in mice that overexpress amyloid precursor protein (APP) (Calhoun et al., 1999, Van Dorpe et al., 2000). APP mice display increased susceptibility to ischemic brain damage (Koistinaho et al., 2002, Zhang et al., 1997). In AD, functional investigations including measurement of cerebral blood flow (CBF) have provided solid evidence for early decline of brain functioning (for review, see Farkas and Luiten, 2001). However, it has not been established whether cerebrovascular abnormalities of AD have functional consequences per se.
We have examined this issue in transgenic mice that overexpress transforming growth factor-β1 (TGF-β1) in astrocytes. TGF-β1 is a multifunctional cytokine implicated in the control of inflammation and tissue repair, which is increased in several neurological diseases including AD (Wyss-Coray et al., 1997; and for review, see Flanders et al., 1998). Astrocytes are key elements associated with vascular cells (Kacem et al., 1998) and synapse metabolism (Pellerin and Magistretti, 2003). Remarkably, overexpression of TGF-β1 in astrocyte results in selective cerebrovascular localization of AD-like alterations (Wyss-Coray et al., 1997). The vascular abnormalities appear sequentially after birth: accumulation of basement membrane proteins and amyloid deposition at 3 months, followed by degeneration of cerebrovascular cells at 9 months. These changes occur in the absence of detectable abnormalities in the parenchyma, such as amyloidosis or synaptodendritic alterations in the cortex or hippocampus (Wyss-Coray et al., 2000a). TGF-β1 transgenic mice thus reflect the cerebral angiopathy of AD or amyloid angiopathy at an early stage (Kalaria and Ballard, 1999), i.e., before intraparenchymal microhemorrhages in humans (Alonzo et al., 1998) or in mouse models (Winkler et al., 2001). In this study, we sought to determine whether cerebrovascular alterations in TGF-β1 transgenic mice were associated with dysfunction of brain circulation. Quantitative autoradiographic measurements of CBF were regionally correlated with vascular abnormalities as visualized by thioflavin-S staining. The results provide evidence for decrements in tissue perfusion in relation to staining of either cerebral vessels or meninges. Molecular analysis of APP expression and Aβ production in the brain of TGF-β1 mice is consistent with the involvement of Aβ peptides in the observed functional changes. Comparison with a previous investigation of cerebral glucose utilization (CGU) in TGF-β1 mice (Wyss-Coray et al., 2000b) shows repercussions on local metabolic rate. The most affected brain regions are those presenting a mismatch between a high energy demand and a limited blood supply, not necessarily those in which blood flow is reduced.
Section snippets
Animals and surgical procedures
Transgenic mice expressing a constitutively active form of TGF-β1 under control of GFAP regulatory sequences have been described previously (Wyss-Coray et al., 1997, Wyss-Coray et al., 2000a). They were heterozygous for the low-expresser line T65. CBF was measured in 9-month-old TGF-β1 mice and nontransgenic littermates. Separate groups of transgenic and nontransgenic littermates of 6–8 months of age were used to analyze APP and amyloid-β peptide expression.
Mice were anesthetized with halothane
Reduced perfusion in cerebral areas with high blood flow in TGF-β1 mice
Absolute values of CBF were significantly lower in several brain regions in TGF-β1 mice compared to nontransgenic littermates (Fig. 1A). These changes cannot be attributed to differences between the physiological parameters of the two experimental groups since none were significant (Table 1). Blood flow reductions were frequent in limbic regions (Fig. 1B), and greatest in the lateral geniculate body of the thalamus (−33%). As regions of high blood flow such as the lateral geniculate body seemed
Reduced brain tissue perfusion is associated with thioflavin-S staining
The highly significant correlation between the number of thioflavin-S-positive vessels and blood flow reductions in the hippocampus and cortex of TGF-β1 mice provides the first strong in vivo evidence for the involvement of a vascular thioflavin-S-related factor in the irrigated regions in close proximity. A first explanation of this result could be that accumulation of fibrillar thioflavin-S-positive material in the cerebral vasculature of TGF-β1 mice has a direct, mechanical effect on blood
Acknowledgments
This work was supported by grants from the CNRS UPR 646, the Université Paris 7, the IFR-6 Circulation-Lariboisière, and by the National Institutes of Health, grants AG15871 (T.W-C). The authors thank Elena Galea for complementary immunohistochemical investigations, Fred Checler for generously providing Aβ antibodies, and Vincent Brossard for expert contribution in data treatment and illustrations.
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