Distinct roles of secreted APP ectodomain variants APPsα and APPsβ in regulation of spine density, synaptic plasticity, and cognition.

Increasing evidence suggests that synaptic functions of the amyloid precursor protein (APP), which is key to Alzheimer pathogenesis, may be carried out by its secreted ectodomain (APPs). The specific roles of APPsα and APPsβ fragments, generated by non-amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APPsα or APPsβ in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2.

Amyloid Precursor Protein Protects Neuronal Network Function after Hypoxia via Control of Voltage-Gated Calcium Channels.

Unlabelled: Acute cerebral ischemia and chronic neurovascular diseases share various common mechanisms with neurodegenerative diseases, such as disturbed cellular calcium and energy homeostasis and accumulation of toxic metabolites. A link between these conditions may be constituted by amyloid precursor protein (APP), which plays a pivotal role in the pathogenesis of Alzheimer's disease, but has also been associated with the response to acute hypoxia and regulation of calcium homeostasis. We therefore studied hypoxia-induced loss of function and recovery upon reoxygenation in hippocampal slices of mice lacking APP (APP(-/-)) or selectively expressing its soluble extracellular domain (APPsα-KI).

Impaired theta-gamma coupling in APP-deficient mice.

Amyloid precursor protein (APP) is critically involved in the pathophysiology of Alzheimer's disease, but its physiological functions remain elusive. Importantly, APP knockout (APP-KO) mice exhibit cognitive deficits, suggesting that APP plays a role at the neuronal network level. To investigate this possibility, we recorded local field potentials (LFPs) from the posterior parietal cortex, dorsal hippocampus and lateral prefrontal cortex of freely moving APP-KO mice.

The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior.

Unlabelled: The amyloid precursor protein family (APP/APLPs) has essential roles for neuromuscular synapse development and for the formation and plasticity of synapses within the CNS. Despite this, it has remained unclear whether APP mediates its functions primarily as a cell surface adhesion and signaling molecule or via its numerous proteolytic cleavage products. To address these questions, we followed a genetic approach and used APPΔCT15 knockin mice lacking the last 15 amino acids of APP, including the highly conserved YENPTY protein interaction motif.

Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer's disease mouse model.

Alzheimer's disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis.

Acute function of secreted amyloid precursor protein fragment APPsα in synaptic plasticity.

The key role of APP in the pathogenesis of Alzheimer disease is well established. However, postnatal lethality of double knockout mice has so far precluded the analysis of the physiological functions of APP and the APLPs in the brain. Previously, APP family proteins have been implicated in synaptic adhesion, and analysis of the neuromuscular junction of constitutive APP/APLP2 mutant mice showed deficits in synaptic morphology and neuromuscular transmission.

Differential role of APP and APLPs for neuromuscular synaptic morphology and function.

The analysis of mouse models indicated that APP and the related APLPs are important for synapse formation and function. The synaptic role of APP is, however, complex due to partially overlapping functions within the gene family. APP/APLPs are proteolytically cleaved and have both adhesive and signaling properties.

Comparative analysis of single and combined APP/APLP knockouts reveals reduced spine density in APP-KO mice that is prevented by APPsα expression.

Synaptic dysfunction and synapse loss are key features of Alzheimer's pathogenesis. Previously, we showed an essential function of APP and APLP2 for synaptic plasticity, learning and memory. Here, we used organotypic hippocampal cultures to investigate the specific role(s) of APP family members and their fragments for dendritic complexity and spine formation of principal neurons within the hippocampus.

Hippocampal network oscillations in APP/APLP2-deficient mice.

The physiological function of amyloid precursor protein (APP) and its two homologues APP-like protein 1 (APLP1) and 2 (APLP2) is largely unknown. Previous work suggests that lack of APP or APLP2 impairs synaptic plasticity and spatial learning. There is, however, almost no data on the role of APP or APLP at the network level which forms a critical interface between cellular functions and behavior.

Functions of the APP gene family in the nervous system: insights from mouse models.

The amyloid precursor protein (APP) plays a key role in the pathogenesis of Alzheimer's disease (AD), as proteolytical cleavage of APP gives rise to the β-amyloid peptide which is deposited in the brains of Alzheimer patients. During the past years, intense research efforts have been directed at elucidating the physiological function(s) of APP and the question of whether a perturbation of these functions contributes to AD pathogenesis. Indeed, a growing body of evidence has accumulated supporting a role of APP and the two closely related homologues APLP1 and APLP2 in various aspects of nervous system development and function, in particular, for synapse formation and function.

APP and APLP2 are essential at PNS and CNS synapses for transmission, spatial learning and LTP.

Despite its key role in Alzheimer pathogenesis, the physiological function(s) of the amyloid precursor protein (APP) and its proteolytic fragments are still poorly understood. Previously, we generated APPsα knock-in (KI) mice expressing solely the secreted ectodomain APPsα. Here, we generated double mutants (APPsα-DM) by crossing APPsα-KI mice onto an APLP2-deficient background and show that APPsα rescues the postnatal lethality of the majority of APP/APLP2 double knockout mice.

Activity requires soluble amyloid precursor protein alpha to promote neurite outgrowth in neural stem cell-derived neurons via activation of the MAPK pathway.

It is known that activity modulates neuronal differentiation in the adult brain but the signalling mechanisms underlying this process remain to be identified. We show here that activity requires soluble amyloid precursor protein (sAPP) to enhance neurite outgrowth of young neurons differentiating from neural stem cells. Inhibition of sAPP secretion and anti-APP antibodies both abolished the effect of depolarization on neurite outgrowth, whereas exogenous sAPPalpha, similar to depolarization, induced neurite elongation.

The secreted beta-amyloid precursor protein ectodomain APPs alpha is sufficient to rescue the anatomical, behavioral, and electrophysiological abnormalities of APP-deficient mice.

It is well established that the proteolytic processing of the beta-amyloid precursor protein (APP) generates beta-amyloid (Abeta), which plays a central role in the pathogenesis of Alzheimer's disease (AD). In contrast, the physiological role of APP and of its numerous proteolytic fragments and the question of whether a loss of these functions contributes to AD are still unknown. To address this question, we replaced the endogenous APP locus by gene-targeted alleles and generated two lines of knock-in mice that exclusively express APP deletion variants corresponding either to the secreted APP ectodomain (APPs alpha) or to a C-terminal (CT) truncation lacking the YENPTY interaction motif (APPdeltaCT15).

Higher frequency of regulatory T cells in the elderly and increased suppressive activity in neurodegeneration.

The involvement of regulatory T cells (Treg) in autoimmune-disease development has been demonstrated. However, their alteration during ageing and age-related diseases has not been thoroughly investigated yet. Alzheimer (AD) and Parkinson disease (PD), are related to protein-misfolding and are accompanied by neuroinflammation.