The molecular mechanism underlying the pathogenesis of the majority of cases of sporadic Alzheimer's disease (AD) is unknown. A history of stroke was found to be associated with development of some AD cases, especially in the presence of vascular risk factors. Reduced cerebral perfusion is a common vascular component among AD risk factors, and hypoxia is a direct consequence of hypoperfusion. Previously we showed that expression of the ␤-site ␤-amyloid precursor protein (APP) cleavage enzyme 1 (BACE1) gene BACE1 is tightly controlled at both the transcriptional and translational levels and that increased BACE1 maturation contributes to the AD pathogenesis in Down's syndrome. Here we have identified a functional hypoxiaresponsive element in the BACE1 gene promoter. Hypoxia up-regulated ␤-secretase cleavage of APP and amyloid-␤ protein (A␤) production by increasing BACE1 gene transcription and expression both in vitro and in vivo. Hypoxia treatment markedly increased A␤ deposition and neuritic plaque formation and potentiated the memory deficit in Swedish mutant APP transgenic mice. Taken together, our results clearly demonstrate that hypoxia can facilitate AD pathogenesis, and they provide a molecular mechanism linking vascular factors to AD. Our study suggests that interventions to improve cerebral perfusion may benefit AD patients.hypoxia-inducible factor 1␣ ͉ amyloid-␤ protein ͉ neuritic plaque ͉ memory deficit ͉ transcription D eposition of amyloid-␤ protein (A␤) in the brain is the hallmark of Alzheimer's disease (AD) pathology (1). A␤, the major component of neuritic plaques, is derived from ␤-amyloid precursor protein (APP) after sequential cleavage by ␤-and ␥-secretase. Early-onset familial AD caused by mutations in APP and in the presenilin 1 and 2 genes accounts for only Ϸ5% of total AD cases. The majority of AD cases are sporadic AD with late onset and have no defined cause. The major risk factors for AD include aging, atherosclerosis, diabetes mellitus, stroke, the ApoE 4 polymorphism, and less education. Recent studies have shown that a history of stroke can increase AD prevalence by Ϸ2-fold among elderly patients (2-6). The risk is highest when stroke is concomitant with atherosclerotic vascular risk factors (7). Patients with stroke or cerebral infarction also show poorer cognitive performance and greater severity of clinical dementia (8). Hypoxia is a direct consequence of hypoperfusion, a common vascular component among the AD risk factors, and may play an important role in AD pathogenesis.Oxygen homeostasis is essential for the development and physiology of an organism. Hypoxia-inducible factor 1 (HIF-1) is the principal molecule regulating oxygen homeostasis (9). HIF-1 is a member of the basic helix-loop-helix transcription factor family, and the basic region of the protein binds specifically to the 5Ј-RCGTG hypoxia-responsive element (HRE) in a gene promoter region. HIF-1 contains an oxygen-regulated expression subunit ␣ (HIF-1␣) and a constitutively expressed subunit ␤ (HIF-1␤) (Arnt). HIF-1␣...

Tissue repair and regenerative medicine address the important medical needs to replace damaged tissue with functional tissue. Most regenerative medicine strategies have focused on delivering biomaterials and cells, yet there is the untapped potential for drug-induced regeneration with good specificity and safety profiles. The Hippo pathway is a key regulator of organ size and regeneration by inhibiting cell proliferation and promoting apoptosis. Kinases MST1 and MST2 (MST1/2), the mammalian Hippo orthologs, are central components of this pathway and are, therefore, strong target candidates for pharmacologically induced tissue regeneration. We report the discovery of a reversible and selective MST1/2 inhibitor, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino)benzenesulfonamide (XMU-MP-1), using an enzyme-linked immunosorbent assay-based high-throughput biochemical assay. The cocrystal structure and the structure-activity relationship confirmed that XMU-MP-1 is on-target to MST1/2. XMU-MP-1 blocked MST1/2 kinase activities, thereby activating the downstream effector Yes-associated protein and promoting cell growth. XMU-MP-1 displayed excellent in vivo pharmacokinetics and was able to augment mouse intestinal repair, as well as liver repair and regeneration, in both acute and chronic liver injury mouse models at a dose of 1 to 3 mg/kg via intraperitoneal injection. XMU-MP-1 treatment exhibited substantially greater repopulation rate of human hepatocytes in the Fah-deficient mouse model than in the vehicle-treated control, indicating that XMU-MP-1 treatment might facilitate human liver regeneration. Thus, the pharmacological modulation of MST1/2 kinase activities provides a novel approach to potentiate tissue repair and regeneration, with XMU-MP-1 as the first lead for the development of targeted regenerative therapeutics.

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