A substantial body of evidence supports the hypothesis of a vascular component in the pathogenesis of Alzheimer's disease (AD). Cerebral hypoperfusion and blood-brain barrier dysfunction have been indicated as key elements of this pathway. Cerebral amyloid angiopathy (CAA) is a cerebrovascular disorder, frequent in AD, characterized by the accumulation of amyloid-β (Aβ) peptide in cerebral bloo...

This study investigated the in vivo properties of two heavy chain antibody fragments (V(H)H), ni3A and pa2H, to differentially detect vascular or parenchymal amyloid-β deposits characteristic for Alzheimer's disease and cerebral amyloid angiopathy. Blood clearance and biodistribution including brain uptake were assessed by bolus injection of radiolabeled V(H)H in APP/PS1 mice or wildtype litter...

Alzheimer's disease is characterized by amyloid-β (Aβ) peptide accumulation in the brain. CALHM1, a cell-surface Ca(2+) channel expressed in brain neurons, has anti-amyloidogenic properties in cell cultures. Here, we show that CALHM1 controls Aβ levels in vivo in the mouse brain through a previously unrecognized mechanism of regulation of Aβ clearance. Using pharmacological and genetic approach...

According to the 'amyloid cascade hypothesis of Alzheimer's disease' first proposed about 16 years ago, the accumulation of Aβ peptides in the human central nervous system (CNS) is the primary influence driving Alzheimer's disease (AD) pathogenesis, and Aβ peptide accretion is the result of an imbalance between Aβ peptide production and clearance. In the last 18 months multiple laboratories hav...

Amyloid fibrils are self-assembled protein aggregates that are formed from unstructured peptides and unfolded proteins. The fibrils are characterized by a universal β-sheet core stabilized with hydrogen bonds, but the overall structure of amyloid fibrils is variable. The milk protein β-lactoglobulin forms amyloid fibrils upon incubation at low pH and high temperature. It is possible to tune the...

BACE1 is a key protease controlling the formation of amyloid β, a peptide hypothesized to play a significant role in the pathogenesis of Alzheimer's disease (AD). Therefore, the development of potent and selective inhibitors of BACE1 has been a focus of many drug discovery efforts in academia and industry. Herein, we report the nonclinical and early clinical development of LY2886721, a BACE1 ac...

Advances in translational research provide key opportunities to explore the physiological and pathological effects of sleep different neurodegenerative diseases. Recent findings suggest that sleep-wakefulness dysfunctions may predispose disorders such as Alzheimer’s disease (AD), vice versa. New theories on link between β-amyloid tau secretion, accumulation clearance, its interaction with hypoc...