Impaired Cognitive Flexibility Induced by Chronic Cerebral Hypoperfusion in the 5XFAD Transgenic Mouse Model of Mixed Dementia

Abstract

Cerebrovascular lesions are widely prevalent in patients with Alzheimer’s disease (AD), but their relationship to the pathophysiology of AD remains poorly understood. An improved understanding of the interaction of cerebrovascular damage with AD is crucial for the development of therapeutic approaches. Herein, we investigated the effects of chronic cerebral hypoperfusion (CCH) in a 5XFAD transgenic (Tg) mouse model of AD. We established CCH conditions in both Tg and non-Tg mice by inducing unilateral common carotid artery occlusion (UCCAO). Cognitive performance in mice was evaluated, and their brain tissue was examined for amyloid-beta (Aβ) pathology to elucidate possible mechanisms. We found that UCCAO-operated Tg mice showed impaired cognitive flexibility in the reversal phase of the hidden-platform water maze task compared to sham-operated Tg mice. Interestingly, UCCAO-operated Tg mice used fewer spatial-cognitive strategies than sham-operated Tg mice during reversal learning. These cognitive deficits were accompanied by increased Aβ plaque burden and Aβ42 levels in the hippocampus and prefrontal cortex, two regions that play essential roles in the regulation of cognitive flexibility. Furthermore, changes in cognitive flexibility are strongly correlated with the expression levels of enzymes related to Aβ clearance, such as neprilysin and insulin-degrading enzymes. These findings suggest that, in 5XFAD mice, impaired cognitive flexibility is related to CCH, and that Aβ clearance might be involved in this process.

Effects of α5 GABAA receptor modulation on social interaction, memory, and neuroinflammation in a mouse model of Alzheimer's disease

“…In reversal probe, transgenic females, independently of treatment, showed higher latencies to find the new platform compared to old one, which could indicate a sex‐dependent impaired cognitive flexibility as reported in different protocols for the reversal probe for 3‐month‐old 5xFAD males 45 and 3‐15‐month old 5xFAD animals of both sexes 46 . PWZ‐029 vs. control‐treated non‐transgenic males showed an enhanced exploration of the old platform, as reflected in the number of entries in the old platform zone and latency to find the old platform, which could be an indicator of cognitive perseverance 47 …”

Mumefural Improves Recognition Memory and Alters ERK-CREB-BDNF Signaling in a Mouse Model of Chronic Cerebral Hypoperfusion

“…UCCAO was performed as previously described [ 14 ]. Briefly, after a 2 cm midline neck incision under anesthesia with 2% isoflurane, the right common carotid artery was carefully isolated and double-ligated using 6–0 silk sutures.…”

“…The Y-maze test was performed to evaluate short-term working memory [ 14 ]. Each mouse was placed at the junction of three identical arms (40 × 10 × 15 cm; length–width–height) and allowed to freely explore for 8 min.…”

Novel mouse model of mixed dementia using chronic cerebral hypoperfusion induced by bilateral carotid artery stenosis

“…[12][13][14] Representative MD animal model has been fully established. 11,15 In particular, when the two subtypes are combined, the disease spectrum or continuum is broad, and their clinical and histological ndings are di cult to justify. Furthermore, the two subtypes have completely different pathological backgrounds, and the experimental design of drugs treating both disease is di cult.…”