Neurovascular Specifications in the Alzheimer-Like Brain of Mice Affected by Focal Cerebral Ischemia: Implications for Future Therapies.

Alzheimer's disease (AD), the most frequent type of dementia, is a prototypical neurodegenerative disease, but shares with stroke certain common risk factors. Consequently, how vascular pathology may modulate AD pathogenesis has gained scientific attention. Therefore, aside from typical features of AD (e.g., amyloid-ß, tau hyperphosphorylation, and cholinergic dysfunction), changes within the 'neurovascular unit' (NVU) are of particular interest. This study focused on cholinergic, choline acetyltransferase (ChAT)-immunopositive, and tyrosine hydroxylase (TH)-containing neurons in association with the vasculature to explore the neurovascular complex of the AD brain affected by stroke. Wild-type and triple-transgenic (3xTg) mice of different ages underwent unilateral permanent focal cerebral ischemia. Histochemical analyses comprised diverse neuronal and vascular NVU components, and markers of AD. Immunofluorescence labeling confirmed the existence of Aß deposits and phospho-tau together with glial reactions and morphologically altered endothelia, visualized by Solanum tuberosum lectin. Twenty-four hours after ischemia induction, immunoreactivities for ChAT and TH declined in the ischemia-affected striatum and, at least in part, in the ischemic border zone and ipsilateral neocortex. Correlation analyses indicated simultaneous degeneration of neuronal and vascular components. A trend for more severe affection of ChAT was observed in younger as compared with older mice. The present findings suggest complex interactions within the NVU of the AD-like brain affected by ischemia, comprising alterations of the cholinergic system in conjunction with vascular pathology. Hence, it may be worthwhile to explore the impact of a cellular stabilization approach on vascular and glial elements in AD in terms of a potential disease-alleviating strategy.

Delayed histochemical alterations within the neurovascular unit due to transient focal cerebral ischemia and experimental treatment with neurotrophic factors.

Current stroke therapy is focused on recanalizing strategies, but neuroprotective co-treatments are still lacking. Modern concepts of the ischemia-affected neurovascular unit (NVU) and surrounding penumbra emphasize the complexity during the transition from initial damaging to regenerative processes. While early treatment with neurotrophic factors was shown to result in lesion size reduction and blood-brain barrier (BBB) stabilization, cellular consequences from these treatments are poorly understood. This study explored delayed cellular responses not only to ischemic stroke, but also to an early treatment with neurotrophic factors. Rats underwent 60 minutes of focal cerebral ischemia. Fluorescence labeling was applied to sections from brains perfused 7 days after ischemia. Analyses focused on NVU constituents including the vasculature, astrocytes and microglia in the ischemic striatum, the border zone and the contralateral hemisphere. In addition to histochemical signs of BBB breakdown, a strong up-regulation of collagen IV and microglia activation occurred within the ischemic core with simultaneous degradation of astrocytes and their endfeet. Activated astroglia were mainly depicted at the border zone in terms of a glial scar formation. Early treatment with pigment epithelium-derived factor (PEDF) resulted in an attenuation of the usually up-regulated collagen IV-immunoreactivity. However, glial activation was not influenced by treatment with PEDF or the epidermal growth factor (EGF). In conclusion, these data on ischemia-induced cellular reactions within the NVU might help to develop treatments addressing the transition from injury towards regeneration. Thereby, the integrity of the vasculature in close relation to neighboring structures like astrocytes appears as a promising target.