APLP2
Amyloid-like protein 2 precursor (APLP-2) (APPH) (Amyloid protein homolog) (CDEI box-binding protein) (CDEBP) [APPL2]
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The amyloid precursor protein (APP) is a member of a conserved gene family that includes the amyloid precursor-like proteins 1 (APLP1) and 2 (APLP2). APP and APLP2 share a high degree of similarity, and have overlapping patterns of spatial and temporal expression in the central and peripheral tissues, in particular at the neuromuscular junction. APP-family knockout (KO) studies have helped elucidate aspects of function and functional redundancy amongst the APP-family members. In the present study, we investigated motor performance of APLP2-KO mice and the effect sex differences and age-related changes have on motor performance. APLP2-KO and WT (on C57Bl6 background) littermates control mice from 8 (young adulthood) to 48 weeks (middle age) were investigated. Analysis of motor neuron and muscle morphology showed APLP2-KO females but not males, had less age-related motor function impairments. We observed age and sex differences in both motor neuron number and muscle fiber size distribution for APLP2-KO mice compared to WT (C57Bl6). These alterations in the motor neuron number and muscle fiber distribution pattern may explain why female APLP2-KO mice have far better motor function behaviour during ageing.
MeSH Terms
- Age Factors
- Aging
- Amyloid beta-Protein Precursor
- Animals
- Female
- Male
- Mice, Inbred C57BL
- Mice, Knockout
- Motor Activity
- Motor Neurons
- Muscle, Skeletal
- Sex Factors
- Spinal Cord
Keywords
- Ageing
- Amyloid precursor protein
- Amyloid precursor-like protein
- Knockout
- Motor neurons
- Sex differences
Amyloid precursor protein knockout mice (APP-KO) have impaired differentiation of amacrine and horizontal cells. APP is part of a gene family and its paralogue amyloid precursor-like protein 2 (APLP2) has both shared as well as distinct expression patterns to APP, including in the retina. Given the impact of APP in the retina we investigated how APLP2 expression affected the retina using APLP2 knockout mice (APLP2-KO). Using histology, morphometric analysis with noninvasive imaging technique and electron microscopy, we showed that APLP2-KO retina displayed abnormal formation of the outer synaptic layer, accompanied with greatly impaired photoreceptor ribbon synapses in adults. Moreover, APLP2-KO displayed a significant decease in ON-bipolar, rod bipolar and type 2 OFF-cone bipolar cells (36, 21 and 63 %, respectively). Reduction of the number of bipolar cells was accompanied with disrupted dendrites, reduced expression of metabotropic glutamate receptor 6 at the dendritic tips and alteration of axon terminals in the OFF laminae of the inner plexiform layer. In contrast, the APP-KO photoreceptor ribbon synapses and bipolar cells were intact. The APLP2-KO retina displayed numerous phenotypic similarities with the congenital stationary night blindness, a non-progressive retinal degeneration disease characterized by the loss of night vision. The pathological phenotypes in the APLP2-KO mouse correlated to altered transcription of genes involved in pre- and postsynatic structure/function, including CACNA1F, GRM6, TRMP1 and Gα0, and a normal scotopic a-wave electroretinogram amplitude, markedly reduced scotopic electroretinogram b-wave and modestly reduced photopic cone response. This confirmed the impaired function of the photoreceptor ribbon synapses and retinal bipolar cells, as is also observed in congenital stationary night blindness. Since congenital stationary night blindness present at birth, we extended our analysis to retinal differentiation and showed impaired differentiation of different bipolar cell subtypes and an altered temporal sequence of development from OFF to ON laminae in the inner plexiform layer. This was associated with the altered expression patterns of bipolar cell generation and differentiation factors, including MATH3, CHX10, VSX1 and OTX2. These findings demonstrate that APLP2 couples retina development and synaptic genes and present the first evidence that APLP2 expression may be linked to synaptic disease.
MeSH Terms
- Aging
- Amacrine Cells
- Amyloid beta-Protein Precursor
- Animals
- Animals, Newborn
- Cell Differentiation
- Complement System Proteins
- Dendrites
- Eye Diseases, Hereditary
- Gene Deletion
- Genetic Diseases, X-Linked
- Mice, Inbred C57BL
- Mice, Knockout
- Myopia
- Neurogenesis
- Night Blindness
- Photoreceptor Cells, Vertebrate
- Presynaptic Terminals
- RNA, Messenger
- Retinal Bipolar Cells
- Synaptic Transmission
- Transcription Factors
- Transcription, Genetic
Keywords
- Amyloid precursor protein
- Amyloid precursor-like protein 2
- Congenital stationary night blindness
- Differentiation
- Synapses
- Synaptopathy
- Transcription
Alterations to the expression of the Amyloid Precursor Protein (APP) and its paralogue Amyloid Precursor-Like Protein 2 (APLP2) affect metal homeostasis in vitro and in vivo. Analysis of the in vivo effects of the APP and APLP2 knockouts on metal homeostasis has been restricted to APP and APLP2 single knockout mice, and up to12 month old animals. To define the redundancy and inter-relationship between the APP and APLP2 genes as regulators of metal homeostasis, and how this is influenced by aging, we investigated copper, iron, zinc and manganese levels in APP and APLP2 single knockout mice as well as homozygous:hemizygous knockout mice at 3, 12 and 18 plus months of age. These studies identified age and genotype dependent changes in metal levels, and established differences in the relative roles played by APP and APLP2 in modulating metal homeostasis.
MeSH Terms
- Aging
- Alzheimer Disease
- Amyloid beta-Protein Precursor
- Animals
- Brain
- Copper
- Gene Deletion
- Homeostasis
- Iron
- Manganese
- Metals, Heavy
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Zinc