Endopeptidases in Alzheimer’s Disease:
Deficiencies in clearance of the Aß peptide are thought to contribute to development of Alzheimer’s disease (AD). The endopeptidase neprilysin (NEP) has been shown to be a key enzyme regulating Aß. However, evidence suggests the existence of other proteases that contribute to the clearing of Aß. Soluble-secreted-endopeptidase (SEP, NEP2, MMEL, NL1, NEPLP) is the closest known homolog to NEP, is expressed in the brain, degrades Aß. Therefore, SEP is a good candidate for an enzyme that cooperates with NEP to control cerebral Aß levels. We have shown that the human homolog of SEP can efficiently degrade Aß42 and Aß40 (Huang et al. 2008). To test the in vivo importance of SEP in Aß clearance, we are upregulating and downregulating SEP and NEP expression by gene transfer and genomic manipulations of mice. Furthermore, in vivo expression levels in mice and humans are being measured to determine if expression is consistent with a role in aging and Alzheimer's. Finally, we are developing and testing forms of SEP that may be useful for therapy of Alzheimer's disease.
LDL Receptors and Alzheimer's Disease:
The most significant risk factor linked with sporadic Alzheimer's is associated with polymorphisms in the apolipoprotein E (apoE) gene. The apoE4 isoform is known to be associated with a 3 (heterozygous) to 8 (homozygous) - fold increase in susceptibility to Alzheimer's. Furthermore, individuals carrying the apoE2 allele are reported to be less susceptible to this disease. Clearly this is an important protein involved in modulating disease pathology. ApoE binds to a family of receptors known as the low-density lipoprotein (LDL) receptors. Binding and uptake of lipoprotein particles into cells is mediated by these LDL-receptor family members (LRFM). However, many of these receptors also mediate or facilitate signal transduction pathways leading to altered protein function and gene expression. Many LRFM modulate aspects of adult neurogenesis. Furthermore, they have been shown to modulate aspects of Alzheimer's pathology, by controlling tau phosphorylation, and Aß production. Therefore there is "cross-talk" between adult neurogenesis and Alzheimer's disease. Using knockout mice and lentiviral gene transfer we are investigating the role of LRFM in neurogenesis and AD.