The role of APP and APLP for synaptic transmission, plasticity, and network function: lessons from genetic mouse models.
ABSTRACT APP, APLP1, and APLP2 form a family of mammalian membrane proteins with unknown function. APP, however, plays a key role in the molecular pathology of Alzheimer's disease (AD), indicating that it is somehow involved in synaptic transmission, synaptic plasticity, memory formation, and maintenance of neurons. At present, most of our knowledge about the function of APP comes from consequences of AD-related mutations. The native role of APP, and even more of APLP1/2, remains largely unknown. New genetic knockout and knockin models involving several members of the APP/APLP family may yield better insight into the synaptic and systemic functions of these proteins. Here, we summarize recent results from such transgenic animals with special emphasis on synaptic plasticity and coherent patterns of memory-related network activity in the hippocampus. Data from APP knockout mice suggest that this protein is needed for the expression of long-term potentiation (LTP) in aged, but not in juvenile mice. The missing function can be rescued by expressing part of the protein, as well as by blocking inhibition. Double knockout mice lacking APP and APLP2 die shortly after birth indicating that different members of the APP/APLP family can mutually compensate for genetic ablation of single proteins. Recent techniques allow for analysis of tissue with combined defects, e.g., by expressing only part of APP in APLP2 knockout mice or by growing stem cells with multiple deletions on normal slice cultures. Data from these experiments confirm that APP and APLP2 do indeed play an important role in synaptic plasticity. Much less is known about the role of APP/APLP at the network level. Coherent patterns of activity like hippocampal network oscillations are believed to support formation and consolidation of memory. Analysis of such activity patterns in tissue from mice with altered expression of APP/APLP has just started and may shed further light on the importance of these proteins for cognitive functions.
- SourceAvailable from: Rodrigo A Cunha[Show abstract] [Hide abstract]
ABSTRACT: Alzheimer's disease (AD) affects almost 35 million people worldwide. One of the neuropathological features of AD is the presence of extracellular amyloid plaques, which are mainly composed of amyloid-β (Aβ) peptides. These peptides derive from the amyloidogenic proteolytic processing of the amyloid-β protein precursor (AβPP), through the sequential action of β- and γ-secretases. However, AβPP can also be cleaved by a non-amyloidogenic pathway, involving an α-secretase, and in this case the Aβ formation is precluded. The production of Aβ and of other AβPP catabolites depends on the spatial and temporal co-localization of AβPP with α- or β-secretases and γ-secretase, which traffic through the secretory pathway in a highly regulated manner. Disturbances on AβPP and secretases intracellular trafficking and, consequently, in their localization may affect dynamic interactions between these proteins with consequences in the AD pathogenesis. In this article, we critically review the recent knowledge about the trafficking and co-localization AβPP and related secretases in the brain under physiological and AD conditions. A particular focus is given to data concerning the distribution of AβPP and secretases in different types of synapses relatively to other neuronal or glial localizations. Furthermore, we discuss some possible signals that govern the dynamic encounter of AβPP with each group of secretases, such as AβPP mutations, estrogen deprivation, chronic stress, metabolic impairment, and alterations in sleep pattern-associated with aging. The knowledge of key signals that are responsible for the shifting of AβPP processing away from α-secretases and toward the β-secretases might be useful to develop AD therapeutic strategies.Journal of Alzheimer's disease: JAD 01/2015; 45(2). DOI:10.3233/JAD-142730 · 3.61 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Amyloid-β protein precursor (AβPP) is a large transmembrane protein highly expressed in the central nervous system and cleavage of it can produce amyloid-β peptides (Aβ) involved in synaptic dysfunction and loss associated with cognitive impairment in Alzheimer's disease (AD). Surprisingly, little is known about the synaptic and sub-synaptic distribution of AβPP in different types of nerve terminals. We used total, synaptic, sub-synaptic, and astrocytic membrane preparations obtained from the hippocampus of adult rats to define the localization of AβPP, using two different antibodies against different AβPP epitopes. Western blot analysis revealed that AβPP was not significantly enriched in synaptosomal as compared to total membranes. Within synapses, AβPP immunoreactivity was more abundant in pre- (60 ± 4%) than post- (30 ± 5%) or extra-synaptic fractions (10 ± 2%). Immunocytochemical analysis of purified nerve terminals indicated that AβPP was more frequently associated with glutamatergic (present in 31 ± 4% of glutamatergic terminals) rather than with GABAergic (16 ± 3%) or cholinergic terminals (4 ± 1%, n = 4). We also observed a general lack of co-localization of AβPP and GFAP immunoreactivities in the hippocampus of sections of adult rat brain, albeit we could detect the presence of AβPP in gliosomes (vesicular specializations of astrocytic membranes), suggesting that AβPP has a heterogeneous localization restricted to certain regions of astrocytes. These results provide the first direct demonstration that AβPP is mostly distributed among glutamatergic rather than GABAergic or cholinergic terminals of the adult rat hippocampus, in remarkable agreement with the particular susceptibility to dysfunction and degeneration of glutamatergic synapses in early AD.Journal of Alzheimer's disease: JAD 02/2014; 40(4). DOI:10.3233/JAD-132030 · 3.61 Impact Factor
- Experimental Brain Research 02/2012; 217(3-4):325-9. DOI:10.1007/s00221-012-3039-2 · 2.17 Impact Factor