Lowering Beta-Amyloid peptide (Ab) levels in the brain may be effective for the treatment of Alzheimer's disease (AD). BACE1 is the enzyme that initiates Ab generation and therefore it is a prime AD drug target. However, the minimum level of BACE1 inhibition for therapeutic effects in vivo, while avoiding mechanism-based toxicities, is unknown. We have generated BACE1 deficient (BACE1-/-) mice and have observed that these mice exhibit memory deficits. BACE1 in presynaptic terminals, suggesting an important BACE1 function at the synapse. BACE1 is also involved in stress pathways. Therefore, it appears that a carefully balanced level of BACE1 inhibition will need to be maintained for therapeutic effect without side-effects. For this project we will breed APP transgenic (Tg), BACE1-/-, and our new tet-inducible BACE1-YFP Tg mice. In the resulting compound Tg mice, we will adjust BACE1 levels in the forebrain from 0% to 100% of endogenous BACE1 levels by feeding mice doxycycline. We will use a combination of molecular genetic, biochemical, cell biological, and behavioral approaches to 1. determine the optimal level of BACE1 inhibition that will maximize therapeutic effects but minimize mechanism-based toxicities, and 2. better understand the function of BACE1 in the brain. Our hypothesis is that a critical level of BACE1 inhibition will alleviate A-dependent cognitive impairment and amyloid pathology, but will not compromise important BACE1 functions.
In Aim 1 we will determine the quantitative relationships between BACE1 level, Ab production, amyloid deposition, and memory deficits in vivo. We will investigate the hypothesis that an optimal level of BACE1 inhibition exists for reducing Ab production, delaying amyloid plaque formation, and rescuing Ab-dependent memory deficits, without completely blocking BACE1. The results of this Aim will provide guidelines for optimal BACE1 inhibitor drug dosing in humans.
In Aim 2, we will determine the role of BACE1 in memory impairment and physiologic stress in vivo. We will test the hypothesis that BACE1 has a function in memory and also participates in stress response in the brain. Finally, we will determine if BACE1-/- mice are compromised following stress and whether resulting neurodegeneration is rescued by BACE1. These studies will provide information about 1. minimum BACE1 levels required to avoid BACE1 mechanism-based toxicities of BACE1 and 2. BACE1 function in brain.
In Aim 3, we will determine the BACE1 compartment within presynaptic terminals, the site of -secretase cleavage in terminals, and the control of BACE1 sorting to terminals. We will investigate the hypothesis that Golgi-localized -ear containing ADP ribosylation factor-binding (GGA) proteins sort BACE1 to the presynaptic terminal where it cleaves APP within synaptic endosomes. These studies will provide insight into the mechanisms of 1. BACE1 targeting to the presynaptic terminal, 2. A generation in the terminal, and 3. BACE1 function at the synapse. Our results are expected to strengthen the conceptual foundation for the development of BACE1 inhibitors for the treatment of AD and provide insight into BACE1 function in vivo.
Alzheimer's disease (AD) is the leading cause of dementia in the elderly, yet there is no disease modifying therapy available. BACE1 is the enzyme that initiates the formation of Ab, the likely cause of AD. In this proposal, we will determine the effects of different levels of BACE1 inhibition on Ab production, the formation of amyloid plaques, and memory deficits in AD mouse models. In addition, we will investigate the effects of BACE1 inhibition on the brain in order to understand potential side-effects of BACE1 inhibitor drugs.
|Buggia-Prévot, Virginie; Fernandez, Celia G; Riordan, Sean et al. (2014) Axonal BACE1 dynamics and targeting in hippocampal neurons: a role for Rab11 GTPase. Mol Neurodegener 9:1|
|Yan, Riqiang; Vassar, Robert (2014) Targeting the ? secretase BACE1 for Alzheimer's disease therapy. Lancet Neurol 13:319-29|
|Vassar, Robert; Kuhn, Peer-Hendrik; Haass, Christian et al. (2014) Function, therapeutic potential and cell biology of BACE proteases: current status and future prospects. J Neurochem 130:4-28|
|Kandalepas, Patty C; Sadleir, Katherine R; Eimer, William A et al. (2013) The Alzheimer's *-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques. Acta Neuropathol 126:329-52|
|Eimer, William A; Vassar, Robert (2013) Neuron loss in the 5XFAD mouse model of Alzheimer's disease correlates with intraneuronal A?42 accumulation and Caspase-3 activation. Mol Neurodegener 8:2|
|De Strooper, Bart; Vassar, Robert; Golde, Todd (2010) The secretases: enzymes with therapeutic potential in Alzheimer disease. Nat Rev Neurol 6:99-107|
|Vassar, Robert; Kovacs, Dora M; Yan, Riqiang et al. (2009) The beta-secretase enzyme BACE in health and Alzheimer's disease: regulation, cell biology, function, and therapeutic potential. J Neurosci 29:12787-94|
|O'Connor, Tracy; Sadleir, Katherine R; Maus, Erika et al. (2008) Phosphorylation of the translation initiation factor eIF2alpha increases BACE1 levels and promotes amyloidogenesis. Neuron 60:988-1009|
|Ohno, Masuo; Cole, Sarah L; Yasvoina, Marina et al. (2007) BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26:134-45|
|Zhao, Jie; Fu, Yifan; Yasvoina, Marina et al. (2007) Beta-site amyloid precursor protein cleaving enzyme 1 levels become elevated in neurons around amyloid plaques: implications for Alzheimer's disease pathogenesis. J Neurosci 27:3639-49|
Showing the most recent 10 out of 12 publications