TABLE 1 | Role of angioneurins in adult neurodegeneration and repair
From the following article:
Neurovascular signalling defects in neurodegeneration
Serena Zacchigna, Diether Lambrechts & Peter Carmeliet
Nature Reviews Neuroscience 9, 169-181 (March 2008)
doi:10.1038/nrn2336
| Angioneurin | Result of loss of function | Result of gain of function | Receptor expression |
|---|---|---|---|
| NGF | AD-like neurodegeneration, including cortical atrophy, memory deficits and amyloid deposits (NGF knockdown)19; hippocampal cholinergic defects and reduced memory acquisition and retention (Ngf+/-)144 | Neuroprotection after protein delivery in clinical trials for AD145, in models of AD, HD and PD146, and in CNS and PNS injury and neuropathy; protective and detrimental roles in epilepsy147 | TrkA, which is expressed by neurons, glial cells, endothelial cells and bone marrow progenitors19 |
| NT3, NT4 and BDNF | Increased hippocampal (Nt4-/-)148 and striatal (Nt3+/-) neuron loss after injury149; loss of serotonergic fibres and impaired LTP (Bdnf+/-)22; increased degeneration of enkephalinergic neurons in HD (Bdnf+/-  R6/1)20; loss of hippocampal spines (TrkB+/-); neuron loss and  -synuclein accumulation in the substantia nigra (TrkB+/- TrkC+/-)21 | Neuroprotective against HD20, PD146, CNS and PNS injury, neuropathy and retinal degeneration; protective and detrimental roles in epilepsy147 | TrkB (the receptor for BDNF and NT4) and TrkC (the receptor for NT3) are expressed by various neural and some endothelial cell populations29, 30 |
| VEGF | Increased risk of ALS in humans27; ALS in mice (Vegf /)63; aggravation of ALS in mSOD1 mice (Vegf/ mSOD1)27; motor-neuron loss in hypoxic mice (spinal VEGFR2 knockdown); motor-neuron axonopathy in mSOD1 zebrafish31; retinal ganglion death (VEGF inhibitors)37 | Delivery of VEGF or VEGFR2, or of the genes that encode them, improves memory and learning and77 provides neuroprotection in models of ALS29, 30, and PD119, in CNS and PNS injury27, and in neuropathy and retinal degeneration37, 150 | VEGF receptors are expressed by endothelial cells, bone marrow progenitors and various neural cell types. VEGFR1 is generally more abundant on glial cells, whereas VEGFR2 is more abundant on neurons27, 29 |
| PDGF | Neuron loss after injury or NMDA excitotoxicity (Pdgfr -/- in neurons)38; reduced oligodendrogliosis in the corpus callosum (Pdgfr+/-)151 | Neuroprotection after protein delivery in models of PD and MS, and in CNS injury38 | PDGFR and PDGFR, which are expressed by vascular pericytes (precursors), neurons, glia and NSCs38 |
| ANG | ALS in humans (ANG mutations)39 | Unknown | ANG binds to receptors on endothelial cells, smooth muscle cells and neurons, but the receptor has not been identified152, 153, 154 |
| FGFs | Impaired neurogenesis, memory and LTP (brain Fgfr1-/-)64; increased myelin production (Fgf2-/- oligodendrocyte Fgfr1DN)74; BBB leakiness (Fgf2-/-)58 | Neuroprotection after protein or gene delivery in models of PD117, HD123, epilepsy and MS125, in CNS and PNS injury74, in neuropathy and in retinal degeneration | FGFR1 and FGFR2 mainly mediate endothelial cell proliferation. FGFRs are expressed by various neural cell types155 |
| TGF1 | Early postnatal neocortical neuron loss (Tgf1-/-); neurodegeneration (neuronal Tgfr2DN); A accumulation and dendrite loss (neuronal Tgfr2DN human APP+)45, 46 | Neuroprotection, reduced inflammation and enhanced A clearance in AD mice (astrocytic Tgf1+ human APP+)49; AD-like angiopathy (astrocytic Tgf1+)47, 48; improved outcome in MS127; variable effects on neuron death in ischaemia or injury models | TGFR1 and TGFR2, which are expressed by neurons, glia, endothelial cells and smooth muscle cells156 |
| IGF1 | Impaired learning and synaptic plasticity (liver Igf1-/-)157; defective remyelination (neuronal Igf1r-/-)110 | Neuroprotection after protein or gene delivery in models of ALS112, AD35 and PD, in CNS and PNS injury, in neuropathy and in aging (retained learning ability and muscle innervation99) | IGF1R is expressed by endothelial cells, smooth muscle cells, neurons and glia110, 158 |
| HGF | Depression and anxiety151 and spontaneous seizures in mice159 | Neuroprotection after protein delivery in models of ALS160 and PD118, in neuropathy161, in CNS injury and in retinal degeneration | MET, which is expressed by endothelial cells and pericytes162, neurons and glia163 |
| EGF | Early postnatal degeneration of forebrain neurons (Egfr-/-)70 | Neuroprotection after protein delivery in models of PD and in CNS injury | EGFRs (ErbB1–4) are expressed by neurons, glia and endothelial cells (ErbB1 is selectively expressed in tumour endothelial cells)70, 164 |
| EPO | Reduced hippocampal neurogenesis (brain Epor-/-)165 | Loss of NMJs and nerve degeneration (Epo+)62; neuroprotection after protein delivery in models of ALS, PD, MS126 and epilepsy166, in CNS and PNS injury167, in neuropathy167 and in retinal degeneration | EPOR, which is expressed by endothelial cells, NSCs, neurons and Schwann cells168 |
| PGRN | FTD and ALS in humans (PGRN mutations)42 | Neuroprotective effects in vitro | Functional receptors not yet identified |
| For each phenotype, the genetic or pharmacological manipulation is indicated between brackets: -/- denotes knockout of both alleles of a gene; -/+ denotes knockout of one allele of a gene; + denotes constitutive overexpression of a gene; DN denotes a dominant-negative mutation. R6/1 mice express exon 1 of the human huntingtin gene with an expanded CAG repeat; Vegf/ mice have a deletion in the hypoxia response element of their Vegf gene; mSOD1 mice carry a mutated form of human SOD1.
AD, Alzheimer's disease; ALS, amyotrophic lateral sclerosis; ANG, angiogenin; APP, amyloid precursor protein; BBB, blood–brain barrier; BDNF, brain-derived neurotrophic factor; EGF, epidermal growth factor; EGFR, EGF receptor; EPO, erythropoietin; EPOR, EPO receptor; FGF, fibroblast growth factor; FGFR, FGF receptor; FTD, frontotemporal dementia; HD, Huntington's disease; HGF, hepatocyte growth factor; IGF1, insulin-like growth factor 1; IGF1R, IGF1 receptor; LTP, long-term potentiation; MET, met proto-oncogene; MS, multiple sclerosis; NMDA, N-methyl-d-aspartate; NGF, nerve growth factor; NMJ, neuromuscular junction; NSC, neural stem cell; NT, neurotrophin; PD, Parkinson's disease; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PGRN, progranulin; SOD1, superoxide dismutase 1; TGF1 transforming growth factor-1; TGFR, TGF1 receptor; VEGF, vascular endothelial growth factor; VEGFR, VEGFR receptor. | |||
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