- Huffington Center on Aging (Office)
- Baylor College of Medicine One Baylor Plaza M320 Houston, Texas 77030 United States
- Baylor College of Medicine
- Huffington Center on Aging
- Huffington Foundation Endowed Chair in Aging
- Baylor College of Medicine
- Houston, Texas, United States
- BS from Peking University
- PhD from Baylor College Of Medicine
- Molecular genetics of Alzheimer’s disease
Alzheimer’s disease (AD) is the leading cause of senile dementia characterized by the beta-amyloid plaque deposition, synaptic dysfunction and loss of neurons, in particular the basal forebrain cholinergic neurons. The major components of the plaques are 40 to 42 amino acid peptides (Ab) derived from proteolytic processing of the amyloid precursor protein (APP). Two classes of genes have been identified that are genetically linked to early onset of AD: APP and presenilins (PS1 and PS2). Mutations in these genes lead to dominant inheritance of familial Alzheimer’s disease (FAD) and are associated with accelerated plaque deposition.
My laboratory has a long-standing interest in AD research using mouse genetics approach. Because of the critical roles of APP and presenilins in AD pathogenesis, our effort has been focused on investigating the physiological functions of APP and presenilins and elucidating the pathogenic mechanisms of the disease-causing mutations. Using the peripheral cholinergic synapse neuromuscular junction (NMJ) as a model system, we identified an essential role of the APP family of proteins in regulating synaptic vesicle availability and synaptic transmission. We recently discovered that it is likely mediated by its regulation of the high affinity choline transporter CHT, a molecule that plays rate-limiting roles in cholinergic neurotransmission, and this activity appears to require APP expression in both pre- and postsynaptic compartments and applies to both NMJ and basal forebrain cholinergic neurons. This finding implies that impaired APP function may directly contribute to cholinergic neuronal vulnerability and AD pathogenesis. Current and future work is directed at deciphering the mechanisms of APP in various neuronal circuitries and investigating the effect of the pathogenic mutations.
Presenilins (PS) are essential for proteolytic processing of APP to generate Ab peptides. As such, PS inhibitors are being actively pursued as a potential therapeutic approach for amyloid intervention and AD treatment. Through similar mechanisms, PS is required to cleave and activate Notch and has been implicated in processing of other type I membrane proteins. Taking advantage of the extensive panel of PS transgenic, gene knockout and knockin mice and our novel PS “rescue” system, we uncovered various novel functions of PS in vivo, including tumorigenesis, kidney organogenesis, and pigmentation. Importantly, we reveal a physiological role of PS in intracellular protein trafficking and establish a partial loss-of-function mechanism by the PS1 FAD mutations. Our follow-up studies support a partial loss-of-function as the underlying mechanism for accelerated plaque deposition as well. We are interested in establishing the relationship between PS-dependent protein processing and intracellular trafficking. These questions are critically important to understand not only PS biology but also AD pathogenesis in general.
- Polito VA, Li H, Martini-Stoica H, Wang B, Yang L, Xu Y, Swartzlander DB, Palmieri M, di Ronza A, Lee VM, Sardiello M, Ballabio A, Zheng H. "Selective clearance of aberrant tau proteins and rescue of neurotoxicity by transcription factor EB." EMBO Mol Med. 2014 July 28;6(9):1142-60. Pubmed PMID: 25069841
- Guo Q, Li H, Gaddam SS, Justice NJ, Robertson CS, Zheng H. "Amyloid Precursor Protein Revisited: NEURON-SPECIFIC EXPRESSION AND HIGHLY STABLE NATURE OF SOLUBLE DERIVATIVES." J Biol Chem. 2012 January 20;287(4):2437-45. Pubmed PMID: 22144675
- Wang B, Harrison W, Overbeek PA, Zheng H. "Transposon mutagenesis with coat color genotyping identifies an essential role for Skor2 in sonic hedgehog signaling and cerebellum development." Development. 2011 October;138(20):4487-97. Pubmed PMID: 21937600
- Peethumnongsin E, Yang L, Kallhoff-Muñoz V, Hu L, Takashima A, Pautler RG, Zheng H. "Convergence of presenilin- and tau-mediated pathways on axonal trafficking and neuronal function." J Neurosci. 2010 October 6;30(40):13409-18. Pubmed PMID: 20926667
- Li H, Wang B, Wang Z, Guo Q, Tabuchi K, Hammer RE, Südhof TC, Zheng H. "Soluble amyloid precursor protein (APP) regulates transthyretin and Klotho gene expression without rescuing the essential function of APP." Proc Natl Acad Sci USA. 2010 October 5;107(40):17362-7. Pubmed PMID: 20855613
- Li H, Wang Z, Wang B, Guo Q, Dolios G, Tabuchi K, Hammer RE, Südhof TC, Wang R, Zheng H. "Genetic dissection of the amyloid precursor protein in developmental function and amyloid pathogenesis." J Biol Chem. 2010 October 1;285(40):30598-605. Pubmed PMID: 20693289
- Yang L, Wang Z, Wang B, Justice NJ, Zheng H. "Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity." J Neurosci. 2009 December 16;29(50):15660-8. Pubmed PMID: 20016080
- Wang Z, Wang B, Yang L, Guo Q, Aithmitti N, Songyang Z, Zheng H. "Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis." J Neurosci. 2009 September 2;29(35):10788-801. Pubmed PMID: 19726636
- Kallhoff-Munoz V, Hu L, Chen X, Pautler RG, Zheng H. "Genetic dissection of gamma-secretase-dependent and -independent functions of presenilin in regulating neuronal cell cycle and cell death." J Neurosci. 2008 October 29;28(44):11421-31. Pubmed PMID: 18971484
- Wang B, Yang L, Wang Z, Zheng H. "Amyolid precursor protein mediates presynaptic localization and activity of the high-affinity choline transporter." Proc Natl Acad Sci USA. 2007 August 28;104(35):14140-5. Pubmed PMID: 17709753