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Carbonic anhydrase inhibition ameliorates Aβ‐induced neurovascular dysfunction in vivo
Author(s) -
Canepa Elisa,
VazquezTorres Rafael,
Debure Ludovic,
Fossati Silvia
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.044221
Subject(s) - neurodegeneration , carbonic anhydrase , mitochondrion , cerebral amyloid angiopathy , in vivo , acetazolamide , chemistry , amyloid precursor protein , endocrinology , alzheimer's disease , pathology , medicine , biochemistry , biology , enzyme , disease , genetics , dementia
Background Cerebral amyloid angiopathy (CAA) is present in about 90% of Alzheimer's disease (AD) cases and is characterized by the vascular accumulation of amyloid beta (mainly Aβ40), or specific mutated variants (such as the Dutch‐Q22) in familiar forms of the disease. Our laboratory has previously demonstrated that brain vascular amyloidosis triggers mitochondrial dysfunction and caspase‐mediated apoptotic pathways activation in neuronal, glial and endothelial cells, in vitro . We have shown that these pathological processes can be prevented by acetazolamide (ATZ) and metazolamide (MTZ), FDA‐approved carbonic anhydrase inhibitors (CAIs) with a well‐known profile of brain delivery. Carbonic anhydrases (CAs) represent a family of enzymes catalyzing the reaction CO 2 + H 2 O ⇄ HCO 3 − + H + . Amongst 15 known isoforms in humans, CA‐VA and ‐VB are solely expressed in mitochondria, while CA‐II translocates to the mitochondria from the cytosol in aging and neurodegeneration. Methods We fed Tg‐SwDI (APP‐Swedish, Dutch, Iowa) mice, which develop fibrillar amyloid deposits primarily in the cerebral microvasculature starting at 6 months, with a CAI‐diet for 8 months (from 8 to 16 months of age). Following behavioral analysis, brains have been harvested for both biochemical and immunohistochemical analysis. Results Brain CA‐VB expression is dramatically increased in Tg animals compared to WT, and the treatment with ATZ and MTZ significantly decreases it. Moreover, CAIs reduce the number of vasculotropic amyloid deposits and GFAP + astrocytes, main pathological features of the disease. In Tg mice, our preliminary data show that Aβ deposition occurs in both endothelial and glial cells, leading to cell‐specific apoptosis detectable as caspase‐3 cleavage. Interestingly, CAI treatment attenuates brain Aβ load measured by Thioflavin S, as well as endothelial and astrocytic Aβ overload and the resulting caspase activation. Furthermore, the pronounced increase of cerebral CD68 + cells in CAIs‐fed animals suggests a boost of the perivascular phagocytic activity that might explain the observed reduction of Aβ deposition. Conclusions This study supports the role of CAs in the endothelial and astrocytic Aβ‐induced cell death and inflammation pathways associated with CAA and AD, indicating CAIs as potential drugs to improve vascular health and provide neuroprotection.