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␣...

Proteolytic processing of the ␤-amyloid precursor protein (APP) at the ␤ site is essential to generate A␤. BACE1, the major ␤-secretase involved in cleaving APP, has been identified as a type 1 membrane-associated aspartyl protease. We have cloned a 2.1-kb fragment upstream of the human BACE1 gene and identified key regions necessary for promoter activity. BACE1 gene expression is controlled by a TATA-less promoter. The region of bp ؊619 to ؉46 is the minimal promoter to control the transcription of the BACE1 gene. Several putative cis-acting elements, such as a GC box, HSF-1, a PU box, AP1, AP2, and lymphokine response element, are found in the 5 flanking region of the BACE1 gene. Transcriptional activation and gel shift assays demonstrated that the BACE1 promoter contains a functional Sp1 response element, and overexpression of the transcription factor Sp1 potentiates BACE gene expression and APP processing to generate A␤. Furthermore, Sp1 knockout reduced BACE1 expression. These results suggest that BACE1 gene expression is tightly regulated at the transcriptional level and that the transcription factor Sp1 plays an important role in regulation of BACE1 to process APP generating A␤ in Alzheimer's disease.Deposition of A␤ in the brain is a central pathological feature of Alzheimer's disease (AD). A␤ is generated from the ␤-amyloid precursor protein (APP), a type 1 transmembrane protein. In the amyloidogenic pathway APP is first cleaved by BACE1 to generate a secreted form of APP (sAPP␤) and a 99-residue membrane-associated fragment (C99). C99 is the substrate of ␥-secretase, and intramembrane cleavage at the ␥ site generates A␤ and CTF␥ fragments. There is also a nonamyloidogenic pathway, where ␣-secretase cleaves APP first within the A␤ domain, precluding A␤ generation. Proteolytic processing of APP at the ␤ site is essential to generate A␤.

Strong epidemiologic evidence suggests an association between Alzheimer disease (AD) and type 2 diabetes. To determine if amyloid beta (Aβ) and hyperphosphorylated tau occurs in type 2 diabetes, pancreas tissues from 21 autopsy cases (10 type 2 diabetes and 11 controls) were analyzed. APP and tau mRNAs were identified in human pancreas and in cultured insulinoma beta cells (INS-1) by RT-PCR. Prominent APP and tau bands were detected by Western blotting in pancreatic extracts. Aggregated Aβ, hyperphosphorylated tau, ubiquitin, apolipoprotein E, apolipoprotein(a), IB1/JIP-1 and JNK1 were detected in Langerhans islets in type 2 diabetic patients. Aβ was co-localized with amylin in islet amyloid deposits. In situ beta sheet formation of islet amyloid deposits was shown by infrared microspectroscopy (SIRMS). LPS increased APP in non-neuronal cells as well. We conclude that Aβ deposits and hyperphosphorylated tau are also associated with type 2 diabetes, highlighting common pathogenetic features in neurodegenerative disorders, including AD and type 2 diabetes and suggesting that Aβ deposits and hyperphosphorylated tau may also occur in other organs than the brain.

Alzheimer's Disease (AD) is the most common neurodegenerative disorder leading to dementia and its prevalence increases with age. The pathological features of AD are characterized by the beta-amyloid protein (A(beta)) deposits in the core of neuritic plaques and abnormal neurofibrillary tangles in the brain of AD patients. BACE1 is the major beta-secretase to cleave the beta-amyloid precursor protein (APP) to generate A(beta). Oxidative stress has been shown to affect A(beta) generation in the AD pathogenesis and the mechanism of such effect is unknown. In this report we generated a novel promoterless enhanced green fluorescent protein (EGFP) reporter gene cloning vector and cloned a 1.9-kb BACE1 gene promoter fragment in this vector. The BACE1 promoter fragment can efficiently activate EGFP or luciferase gene transcription. Oxidative stress induced by hydrogen peroxide resulted in significant increase in the BACE1 promoter activity. Furthermore, hydrogen peroxide treatment facilitated beta-secretase activity and A(beta) generation. Thus, upregulation of BACE1 transcription by oxidative stress may contribute to the pathogenesis of Alzheimer's disease.

Neuritic plaques in the brains are one of the pathological hallmarks of Alzheimer ' s disease (AD). Amyloid ␤ -protein (A ␤ ), the central component of neuritic plaques, is derived from ␤ -amyloid precursor protein (APP) after ␤ -and ␥ -secretase cleavage. The molecular mechanism underlying the pathogenesis of AD is not yet well defi ned, and there has been no effective treatment for AD. Valproic acid (VPA) is one of the most widely used anticonvulsant and mood-stabilizing agents for treating epilepsy and bipolar disorder. We found that VPA decreased A ␤ production by inhibiting GSK-3 ␤ -mediated ␥ -secretase cleavage of APP both in vitro and in vivo. VPA treatment signifi cantly reduced neuritic plaque formation and improved memory defi cits in transgenic AD model mice. We also found that early application of VPA was important for alleviating memory defi cits of AD model mice. Our study suggests that VPA may be benefi cial in the prevention and treatment of AD.