mucke lab

Neurotrophic and Neuroprotective Functions of APP

Excitoprotective
APPs are expressed in multiple organs and cell types. Their conservation across species, their abundance in the brain, and the association of various APP missense mutations with autosomal dominant forms of familial AD (FAD) all suggest important functions for APPs in the CNS. We have focused on the role of APPs in excitotoxic injury and apoptotic death of neurons. Our analysis of transgenic mice in which human APP (hAPP) was expressed from the neuron-specific enolase (NSE) promoter revealed that neuronal overexpression of APP at moderate (near physiological) levels increases the number of presynaptic terminals as well as the expression of growth-associated markers in the neocortex and protects neurons against both acute and chronic excitotoxic injury. Interestingly, hAPP expression increased the uptake of excitatory amino acid neurotransmitters in brains of NSE-hAPP mice, and subsequent cell culture studies revealed that the a-secretase processed N-terminal domain of hAPP stimulates the astroglial uptake of excitatory amino acids via protein kinase A and C-dependent pathways. This APP function may help prevent excess accumulation of potentially excitotoxic amino acids around the synaptic cleft and could explain, at least in part, the excitoprotective effects of hAPP we observed in the NSE-hAPP model. However, high levels of hAPP expression, as found in Down’s syndrome and hAPP transgenic mice, might also sequester essential neurotransmitters into astrocytes and thereby contribute to cognitive deficits. Ongoing studies focus on the identification of APP receptors and on the molecular mechanisms that underlie the APP-mediated stimulation of neurotransmitter transporters.

Antiapoptotic
APP also appears to be involved in the control of apoptosis, the active molecular suicide process that results from the activation of cell death programs. While apoptosis fulfills many important functions (for example, elimination of precancerous cells), the aberrant induction of apoptosis by diseases can have dire consequences if it involves important cells that are largely irreplaceable, such as neurons. Indeed, apoptosis may contribute to diverse neurological diseases, including AD, stroke, and amyotrophic lateral sclerosis. Because some inhibitors of apoptotic pathways can prevent cell death even in the continued presence of the apoptosis-inducing trigger, these pathways are attractive targets for therapeutic intervention. The oncosuppressor protein, p53, functions as a critical molecular switch between life and death at the cellular level. Expression of p53 in neurons increases after brain injury, and several studies indicate that loss of this factor prevents, while overexpression induces, neuronal apoptosis. Therefore, molecules that block the activation of p53 could regulate cell survival and may be particularly important for protecting neurons against apoptosis-inducing injuries. We recently found that APP is such a molecule. Expression of normal (‘wild-type’) hAPP protected neuronal cells against apoptosis, inhibiting the p53-induced suicide process in cell cultures. In contrast, mutant forms of APP carrying amino acid substitutions associated with FAD did not provide this protection. Ongoing studies aim to answer the following key questions: How exactly does APP control the p53 pathway? Do FAD-mutant APPs have a diminished anti-apoptotic capacity because the mutations directly impair their protective function(s) or because the mutations increase the Aβ42 peptide,which may somehow counteract their inhibitory effects on the p53 pathway? How relevant are these processes to the neuronal degeneration in brains of patients with AD?