Table 2.
Summary of major neurotrophic and neurotoxic properties of APP and APP-derived fragments
| Normal functions/neurotrophic properties | Neurotoxic properties | Primary site of action (proposed) | |
|---|---|---|---|
| FL-APP | Cell adhesion | Neurodegeneration when over-expressed | Extracellular space |
| Cell surface receptor (via cytoplasmic domain) | Neurodegenerative changes in APP triplication (trisomy 21 in humans and trisomy 16 in mice) | ||
| Promote cell division | |||
| Promote synapse formation and maintenance | |||
| Promote synaptic plasticity | |||
| Iron transport | |||
| Neuroprotective (to Aβ and glutamate toxicity) | |||
| Aβs | Transcription factor | Inhibition of LTP and synaptic transmission by low-n soluble Aβ oligomers | Extracellular and intracellular spaces |
| Kinase activation | |||
| Cholesterol transport | Synaptic injury | ||
| Antimicrobial | Cognitive impairment | ||
| Neuroprotective against oxidative stress (Aβ40) | |||
| Promote neurogenesis and neurite outgrowth (Aβ40) | |||
| p3 | None reported | Cytotoxic in culture | Extracellular space |
| Promote inflammatory responses | |||
| sAPPα | Trophic properties in neurons and non-neural cells | Unregulated cell growth (promote tumorigenesis) | Extracellular space |
| Neuroprotective | Stimulate microglia activation | ||
| Promote stem cell proliferation | Produce proinflammatory products | ||
| Enhance memory functions | |||
| sAPPβ | Similar to sAPPα (100 fold less potent) | Similar to sAPPα | Extracellular space |
| CTFα | Steer the system away from the amyloidogenic pathway | None reported | Intracellular space |
| CTFβs | None reported | Cytotoxicity to neurons and non-neural cells | Intracellular space |
| Neurotoxic following direct intracranial injection | |||
| Perturb ion channel activities and homeostasis | |||
| Promote astrogliosis | |||
| LTP impairment | |||
| Cognitive impairment | |||
| AICDs | Mediate transcriptional activity | Pro-apoptotic | Intracellular space, nucleus |
| Activity may be dependent on translational modification at YENPTY motif and interaction with cytosolic adaptor molecules | Activate GSK-3β to induce toxicity | ||
| Degeneration in hippocampal neurons | |||
| Induce aberrant electrical activity and silent seizures | |||
| Cognitive impairment | |||
| Jcasp | None reported | Pro-apoptotic | Intracellular space |
| C31 | None reported | Pro-apoptotic, neurotoxic | Intracellular space |
| Generated following caspase cleavage | |||
| Toxicity is APP dependent |