Abnormal accumulation of amyloid-? peptide (A?), which is generated from amyloid precursor protein (APP) through two sequential proteolytic cleavages by BACE1 and ?-secretase, is widely regarded as having a causal role in the development of Alzheimer's disease (AD). Individuals with Down syndrome (DS), due to an extra copy of chromosome 21 in which APP is located at 21q21, develop age-related cognitive decline and AD dementia by 30-40 years earlier than in the general population, and their brains invariantly develop amyloid plaques. Since cleavage of APP by BACE1 initiates the production of A?, inhibition of BACE1 activity should decrease the formation of A? and is therefore a therapeutic target for AD. For the safe use of BACE1 inhibitors in humans, it is very important to fully understand the biological functions of BACE1 in the adult. Notably, neonatal BACE1-null mice have reduced body sizes and survival rates when compared to their age-matched wild-type littermates. However, the death rate is significantly decreased if BACE1-null mice can survive beyond postnatal day 10 and the differences in body weight become much smaller between BACE1-null and wild-type mice over time. In the adult, BACE1-null mice are fertile but do develop multiple mild to moderate phenotypes such as increases in the incidence of epileptic seizures, schizophrenia-like behaviors, retinal pathology, deficits in activity-dependent CA3 synaptic transmission, defects in axonal guidance and impaired myelination in BACE1-null mice. One potential explanation for these phenotypes in BACE1-null mice is the carryover effect from early developmental defects. To determine whether BACE1 is required for normal functions in adult mice, we have generated conditional BACE1 knockout mice and will delete BACE1 in the adult mouse. This new mouse model will allow us to answer questions such as whether inhibition of BACE1 activity in adult is safe and whether BACE1 inhibition at late ages will still e effective in removing preexisting amyloid plaques. This model will also be practical to answer the question of whether BACE1 inhibition in the adult will ameliorate tau pathology. Our central hypothesis in this proposal is that controlled inhibition of BACE1 activity will have optimal effecs on reducing or reversing AD pathologies. By testing our hypothesis, we will perform experiments in three specific aims.
Aim 1 : To characterize BACE1 conditional KO mice and to determine whether induced BACE1 deficiency will lead to phenotypic changes similar to those observed in BACE1-null mice.
Aim 2 : To determine whether induced BACE1 deficiency can reverse pre-formed amyloid plaques in AD transgenic mouse brains.
Aim 3 : to examine whether BACE1 inhibition will impact cognitive function in the Ts65Dn Down syndrome mouse model. The knowledge gained from this study will allow us to answer many unmet questions such as whether a significant reduction of BACE1 in the adult would have beneficial effects for reducing or eliminating AD and DS pathologies.
|Hu, Xiangyou; Das, Brati; Hou, Hailong et al. (2018) BACE1 deletion in the adult mouse reverses preformed amyloid deposition and improves cognitive functions. J Exp Med 215:927-940|
|Hu, Xiangyou; Hou, Hailong; Bastian, Chinthasagar et al. (2017) BACE1 regulates the proliferation and cellular functions of Schwann cells. Glia 65:712-726|
|Shi, Qi; Ge, Yingying; He, Wanxia et al. (2017) RTN1 and RTN3 protein are differentially associated with senile plaques in Alzheimer's brains. Sci Rep 7:6145|
|Hou, Hailong; Fan, Qingyuan; He, Wanxia et al. (2017) BACE1 Deficiency Causes Abnormal Neuronal Clustering in the Dentate Gyrus. Stem Cell Reports 9:217-230|
|Hu, Xiangyou; Fan, Qingyuan; Hou, Hailong et al. (2016) Neurological dysfunctions associated with altered BACE1-dependent Neuregulin-1 signaling. J Neurochem 136:234-49|
|Yan, Riqiang; Fan, Qingyuan; Zhou, John et al. (2016) Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer's disease. Neurosci Biobehav Rev 65:326-40|
|Sharoar, M G; Shi, Q; Ge, Y et al. (2016) Dysfunctional tubular endoplasmic reticulum constitutes a pathological feature of Alzheimer's disease. Mol Psychiatry 21:1263-71|
|Yan, Riqiang (2016) Stepping closer to treating Alzheimer's disease patients with BACE1 inhibitor drugs. Transl Neurodegener 5:13|
|Hu, Xiangyou; Hu, Jinxuan; Dai, Lu et al. (2015) Axonal and Schwann cell BACE1 is equally required for remyelination of peripheral nerves. J Neurosci 35:3806-14|
|He, Wanxia; Hu, Jinxuan; Xia, Yuxing et al. (2014) ?-site amyloid precursor protein cleaving enzyme 1(BACE1) regulates Notch signaling by controlling the cleavage of Jagged 1 (Jag1) and Jagged 2 (Jag2) proteins. J Biol Chem 289:20630-7|