Deletion of p75NTR rescues the synaptic but not the inflammatory status in the brain of a mouse model for Alzheimer's disease.

Introduction: Alzheimer's disease (AD), is characterized by a gradual cognitive decline associated with the accumulation of Amyloid beta (Aß)-oligomers, progressive neuronal degeneration and chronic neuroinflammation. Among the receptors shown to bind and possibly transduce the toxic effects of Aß-oligomers is the p75 neurotrophin receptor (p75NTR). Interestingly, p75NTR mediates several crucial processes in the nervous system, including neuronal survival and apoptosis, maintenance of the neuronal architecture, and plasticity. Furthermore, p75NTR is also expressed in microglia, the resident immune cells of the brain, where it is markedly increased under pathological conditions. These observations indicate p75NTR as a potential candidate for mediating Aß-induced toxic effects at the interface between the nervous and the immune system, thereby potentially participating in the crosstalk between these two systems. Methods: Here we used APP/PS1 transgenic mice (APP/PS1tg) and compared the Aß-induced alterations in neuronal function, chronic inflammation as well as their cognitive consequences between 10 months old APP/PS1tg and APP/PS1tg x p75NTRexonIV knockout mice. Results: Electrophysiological recordings show that a loss of p75NTR rescues the impairment in long-term potentiation at the Schaffer collaterals in the hippocampus of APP/PS1tg mice. Interestingly, however loss of p75NTR does not influence the severity of neuroinflammation, microglia activation or the decline in spatial learning and memory processes observed in APP/PS1tg mice. Conclusion: Together these results indicate that while a deletion of p75NTR rescues the synaptic defect and the impairment in synaptic plasticity, it does not affect the progression of the neuroinflammation and the cognitive decline in a mouse model for AD.

Actions of the TrkB Agonist Antibody ZEB85 in Regulating the Architecture and Synaptic Plasticity in Hippocampal Neurons.

Signaling of BDNF via its TrkB receptor is crucial in regulating several critical aspects of the architecture and function of neurons both during development and in the adult central nervous system. Indeed, several neurological conditions, such as neurodevelopmental and neurodegenerative disorders are associated with alterations both in the expression levels of BDNF and TrkB, and in their intracellular signaling. Thus, the possibility of promoting BDNF/TrkB signaling has become relevant as a potential therapeutic intervention for neurological disorders. However, the clinical potential of BDNF itself has been limited due to its restricted diffusion rate in biological tissue, poor bioavailability and pharmacological properties, as well as the potential for unwanted side effects due to its ability to also signal via the p75NTR pathway. Several small molecule and biologic drug candidate TrkB agonists have been developed and are reported to have effects in rescuing both the pathological alterations and disease related symptoms in mouse models of several neurological diseases. However, recent side-by-side comparative studies failed to show their specificity for activating TrkB signaling cascades, suggesting the need for the generation and validation of improved candidates. In the present study, we examine the ability of the novel, fully human TrkB agonist antibody ZEB85 to modulate the architecture, activity and synaptic plasticity of hippocampal murine neurons under physiological conditions. Moreover, we show here that ZEB85 prevents ß-amyloid toxicity in cultured hippocampal neurons, in a manner which is comparable to BDNF.

Nogo-A Modulates the Synaptic Excitation of Hippocampal Neurons in a Ca2+-Dependent Manner.

A tight regulation of the balance between inhibitory and excitatory synaptic transmission is a prerequisite for synaptic plasticity in neuronal networks. In this context, the neurite growth inhibitor membrane protein Nogo-A modulates synaptic plasticity, strength, and neurotransmitter receptor dynamics. However, the molecular mechanisms underlying these actions are unknown. We show that Nogo-A loss-of-function in primary mouse hippocampal cultures by application of a function-blocking antibody leads to higher excitation following a decrease in GABAARs at inhibitory and an increase in the GluA1, but not GluA2 AMPAR subunit at excitatory synapses. This unbalanced regulation of AMPAR subunits results in the incorporation of Ca2+-permeable GluA2-lacking AMPARs and increased intracellular Ca2+ levels due to a higher Ca2+ influx without affecting its release from the internal stores. Increased neuronal activation upon Nogo-A loss-of-function prompts the phosphorylation of the transcription factor CREB and the expression of c-Fos. These results contribute to the understanding of the molecular mechanisms underlying the regulation of the excitation/inhibition balance and thereby of plasticity in the brain.

Signaling via the p75 neurotrophin receptor facilitates amyloid-ß-induced dendritic spine pathology.

Synapse and dendritic spine loss induced by amyloid-ß oligomers is one of the main hallmarks of the early phases of Alzheimer's disease (AD) and is directly correlated with the cognitive decline typical of this pathology. The p75 neurotrophin receptor (p75NTR) binds amyloid-ß oligomers in the nM range. While it was shown that µM concentrations of amyloid-ß mediate cell death, the role and intracellular signaling of p75NTR for dendritic spine pathology induced by sublethal concentrations of amyloid-ß has not been analyzed. We describe here p75NTR as a crucial binding partner in mediating effects of soluble amyloid-ß oligomers on dendritic spine density and structure in non-apoptotic hippocampal neurons. Removing or over-expressing p75NTR in neurons rescues or exacerbates the typical loss of dendritic spines and their structural alterations observed upon treatment with nM concentrations of amyloid-ß oligomers. Moreover, we show that binding of amyloid-ß oligomers to p75NTR activates the RhoA/ROCK signaling cascade resulting in the fast stabilization of the actin spinoskeleton. Our results describe a role for p75NTR and downstream signaling events triggered by binding of amyloid-ß oligomers and causing dendritic spine pathology. These observations further our understanding of the molecular mechanisms underlying one of the main early neuropathological hallmarks of AD.

BDNF signaling during the lifetime of dendritic spines.

Dendritic spines are tiny membrane specialization forming the postsynaptic part of most excitatory synapses. They have been suggested to play a crucial role in regulating synaptic transmission during development and in adult learning processes. Changes in their number, size, and shape are correlated with processes of structural synaptic plasticity and learning and memory and also with neurodegenerative diseases, when spines are lost. Thus, their alterations can correlate with neuronal homeostasis, but also with dysfunction in several neurological disorders characterized by cognitive impairment. Therefore, it is important to understand how different stages in the life of a dendritic spine, including formation, maturation, and plasticity, are strictly regulated. In this context, brain-derived neurotrophic factor (BDNF), belonging to the NGF-neurotrophin family, is among the most intensively investigated molecule. This review would like to report the current knowledge regarding the role of BDNF in regulating dendritic spine number, structure, and plasticity concentrating especially on its signaling via its two often functionally antagonistic receptors, TrkB and p75NTR. In addition, we point out a series of open points in which, while the role of BDNF signaling is extremely likely conclusive, evidence is still missing.

Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner.

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.

Fast Regulation of GABAAR Diffusion Dynamics by Nogo-A Signaling.

Precisely controlling the excitatory and inhibitory balance is crucial for the stability and information-processing ability of neuronal networks. However, the molecular mechanisms maintaining this balance during ongoing sensory experiences are largely unclear. We show that Nogo-A signaling reciprocally regulates excitatory and inhibitory transmission. Loss of function for Nogo-A signaling through S1PR2 rapidly increases GABAAR diffusion, thereby decreasing their number at synaptic sites and the amplitude of GABAergic mIPSCs at CA3 hippocampal neurons. This increase in GABAAR diffusion rate is correlated with an increase in Ca2+ influx and requires the calcineurin-mediated dephosphorylation of the γ2 subunit at serine 327. These results suggest that Nogo-A signaling rapidly strengthens inhibitory GABAergic transmission by restricting the diffusion dynamics of GABAARs. Together with the observation that Nogo-A signaling regulates excitatory transmission in an opposite manner, these results suggest a crucial role for Nogo-A signaling in modulating the excitation and inhibition balance to restrict synaptic plasticity.

Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.

Purkinje cells (PCs) are primarily affected in neurodegenerative spinocerebellar ataxias (SCAs). For generating animal models for SCAs, genetic regulatory elements specifically targeting PCs are required, thereby linking pathological molecular effects with impaired function and organismic behavior. Because cerebellar anatomy and function are evolutionary conserved, zebrafish represent an excellent model to study SCAs in vivo We have isolated a 258 bp cross-species PC-specific enhancer element that can be used in a bidirectional manner for bioimaging of transgene-expressing PCs in zebrafish (both sexes) with variable copy numbers for tuning expression strength. Emerging ectopic expression at high copy numbers can be further eliminated by repurposing microRNA-mediated posttranslational mRNA regulation.Subsequently, we generated a transgenic SCA type 13 (SCA13) model, using a zebrafish-variant mimicking a human pathological SCA13R420H mutation, resulting in cell-autonomous progressive PC degeneration linked to cerebellum-driven eye-movement deficits as observed in SCA patients. This underscores that investigating PC-specific cerebellar neuropathologies in zebrafish allows for interconnecting bioimaging of disease mechanisms with behavioral analysis suitable for therapeutic compound testing.SIGNIFICANCE STATEMENT SCA13 patients carrying a KCNC3R420H allele have been shown to display mid-onset progressive cerebellar atrophy, but genetic modeling of SCA13 by expressing this pathogenic mutant in different animal models has not resulted in neuronal degeneration so far; likely because the transgene was expressed in heterologous cell types. We developed a genetic system for tunable PC-specific coexpression of several transgenes to manipulate and simultaneously monitor cerebellar PCs. We modeled a SCA13 zebrafish accessible for bioimaging to investigate disease progression, revealing robust PC degeneration, resulting in impaired eye movement. Our transgenic zebrafish mimicking both neuropathological and behavioral changes manifested in SCA-affected patients will be suitable for investigating causes of cerebellar diseases in vivo from the molecular to the behavioral level.

Publisher Correction: ß-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration.

In this Article, owing to an error during the production process, the y-axis label of Fig. 2c should read "Number of Tß-syn cells" rather than "Number of T1ß-syn cells" and the left and right panels of Fig. 4 should be labelled 'a' and 'b', respectively. These errors have been corrected online.

ß-Synuclein-reactive T cells induce autoimmune CNS grey matter degeneration.

The grey matter is a central target of pathological processes in neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. The grey matter is often also affected in multiple sclerosis, an autoimmune disease of the central nervous system. The mechanisms that underlie grey matter inflammation and degeneration in multiple sclerosis are not well understood. Here we show that, in Lewis rats, T cells directed against the neuronal protein ß-synuclein specifically invade the grey matter and that this is accompanied by the presentation of multifaceted clinical disease. The expression pattern of ß-synuclein induces the local activation of these T cells and, therefore, determined inflammatory priming of the tissue and targeted recruitment of immune cells. The resulting inflammation led to significant changes in the grey matter, which ranged from gliosis and neuronal destruction to brain atrophy. In humans, ß-synuclein-specific T cells were enriched in patients with chronic-progressive multiple sclerosis. These findings reveal a previously unrecognized role of ß-synuclein in provoking T-cell-mediated pathology of the central nervous system.

p75NTR regulates brain mononuclear cell function and neuronal structure in Toxoplasma infection-induced neuroinflammation.

Neurotrophins mediate neuronal growth, differentiation, and survival via tropomyosin receptor kinase (Trk) or p75 neurotrophin receptor (p75NTR ) signaling. The p75NTR is not exclusively expressed by neurons but also by certain immune cells, implying a role for neurotrophin signaling in the immune system. In this study, we investigated the effect of p75NTR on innate immune cell behavior and on neuronal morphology upon chronic Toxoplasma gondii (T. gondii) infection-induced neuroinflammation. Characterization of the immune cells in the periphery and central nervous system (CNS) revealed that innate immune cell subsets in the brain upregulated p75NTR upon infection in wild-type mice. Although cell recruitment and phagocytic capacity of p75NTRexonIV knockout (p75-/- ) mice were not impaired, the activation status of resident microglia and recruited myeloid cell subsets was altered. Importantly, recruited mononuclear cells in brains of infected p75-/- mice upregulated the production of the cytokines interleukin (IL)-10, IL-6 as well as IL-1α. Protein levels of proBDNF, known to negatively influence neuronal morphology by binding p75NTR , were highly increased upon chronic infection in the brain of wild-type and p75-/- mice. Moreover, upon infection the activated immune cells contributed to the proBDNF release. Notably, the neuroinflammation-induced changes in spine density were rescued in the p75-/- mice. In conclusion, these findings indicate that neurotrophin signaling via the p75NTR affects innate immune cell behavior, thus, influencing the structural plasticity of neurons under inflammatory conditions.

Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons.

Brain-derived neurotrophin factor (BDNF) has been implicated in neuronal survival, differentiation and activity-dependent synaptic plasticity in the central nervous system. It was suggested that during postnatal development BDNF regulates neuronal architecture and spine morphology of neurons within certain brain areas but not others. Particularly striking are the differences between striatum, cortex and hippocampus. Whether this is due to region- or cell type-specific effects is so far not known. We address this question using conditional bdnf knock-out mice to analyze neuronal architecture and spine morphology of pyramidal cortical and hippocampal neurons as well as inhibitory neurons from these brain areas and excitatory granule neurons from the dentate gyrus. While hippocampal and cortical inhibitory neurons and granule cells of the dentate gyrus are strongly impaired in their architecture, pyramidal neurons within the same brain regions only show a mild phenotype. We found a reduced TrkB phosphorylation within hippocampal interneurons and granule cells of the dentate gyrus, accompanied by a significant decrease in dendritic complexity. In contrast, in pyramidal neurons both TrkB phosphorylation and neuronal architecture are not altered. The results suggest diverse levels of responsiveness to BDNF for different hippocampal and cortical neuronal populations within the same brain area. Among the possible mechanisms mediating these differences in BDNF function, we tested whether zinc might be involved in TrkB transactivation specifically in pyramidal neurons. We propose that a BDNF-independent transactivation of TrkB receptor may be able to compensate the lack of BDNF signaling to modulate neuronal morphology in a cell type-specific manner.

Nogo-A regulates spatial learning as well as memory formation and modulates structural plasticity in the adult mouse hippocampus.

Behavioral learning has been shown to involve changes in the function and structure of synaptic connections of the central nervous system (CNS). On the other hand, the neuronal circuitry in the mature brain is characterized by a high degree of stability possibly providing a correlate for long-term storage of information. This observation indicates the requirement for a set of molecules inhibiting plasticity and promoting stability thereby providing temporal and spatial specificity to plastic processes. Indeed, signaling of Nogo-A via its receptors has been shown to play a crucial role in restricting activity-dependent functional and structural plasticity in the adult CNS. However, whether Nogo-A controls learning and memory formation and what are the cellular and molecular mechanisms underlying this function is still unclear. Here we show that Nogo-A signaling controls spatial learning and reference memory formation upon training in the Morris water maze and negatively modulates structural changes at spines in the mouse hippocampus. Learning processes and the correlated structural plasticity have been shown to involve changes in excitatory as well as in inhibitory neuronal connections. We show here that Nogo-A is highly expressed not only in excitatory, but also in inhibitory, Parvalbumin positive neurons in the adult hippocampus. By this means our current and previous data indicate that Nogo-A loss-of-function positively influences spatial learning by priming the neuronal structure to a higher plasticity level. Taken together our results link the role of Nogo-A in negatively regulating plastic processes to a physiological function in controlling learning and memory processes in the mature hippocampus and open the interesting possibility that it might mainly act by controlling the function of the hippocampal inhibitory circuitry.

Nogo-66 Restricts Synaptic Strengthening via Lingo1 and the ROCK2-Cofilin Pathway to Control Actin Dynamics.

Nogo-A restricts long-term potentiation (LTP) at the Schaffer collateral-CA1 pathway in the adult hippocampus via 2 extracellular domains: Nogo-A-Δ20 and Nogo-66. Nogo-66 signals via Nogo Receptor 1 (NgR1) to regulate synaptic function. Whether the NgR1 coreceptors Lingo1 and p75NTR are involved in the signaling in this context is still not known. Moreover, the intracellular cascade mediating the activity of Nogo-66 in restricting LTP is unexplored. We combine electrophysiology and biochemistry in acute hippocampal slices and demonstrate that a loss of function for Lingo1 results in a significant increase in LTP levels at the Schaffer collateral-CA1 pathway, and that Lingo1 is the NgR1 coreceptor mediating the role of Nogo-66 in restricting LTP. Our data show that p75NTR is not involved in mediating the Nogo-66 effect on LTP. Moreover, loss of function for p75NTR and NgR1 equally attenuate LTD, suggesting that p75NTR might mediate the NgR1-dependent regulation of LTD, independently of Nogo-66. Finally, our results indicate that Nogo-66 signaling limits LTP via the ROCK2-Cofilin pathway to control the dynamics of the actin cytoskeleton. The present results elucidate the signaling pathway activated by Nogo-66 to control LTP and contribute to the understanding of how Nogo-A stabilizes the neural circuits to limit activity-dependent plasticity events in the mature hippocampus.

Nogo-A controls structural plasticity at dendritic spines by rapidly modulating actin dynamics.

Nogo-A and its receptors have been shown to control synaptic plasticity, including negatively regulating long-term potentiation (LTP) in the cortex and hippocampus at a fast time scale and restraining experience-dependent turnover of dendritic spines over days. However, the molecular mechanisms and the precise time course mediating these actions of Nogo-A are largely unexplored. Here we show that Nogo-A signaling in the adult nervous system rapidly modulates the spine actin cytoskeleton within minutes to control structural plasticity at dendritic spines of CA3 pyramidal neurons. Indeed, acute Nogo-A loss-of-function transiently increases F-actin stability and results in an increase in dendritic spine density and length. In addition, Nogo-A acutely restricts AMPAR insertion and mEPSC amplitude at hippocampal synaptic sites. These data indicate a crucial function of Nogo-A in modulating the very tight balance between plasticity and stability of the neuronal circuitry underlying learning processes and the ability to store long-term information in the mature CNS. © 2016 Wiley Periodicals, Inc.

Two-Photon Correlation Spectroscopy in Single Dendritic Spines Reveals Fast Actin Filament Reorganization during Activity-Dependent Growth.

Two-photon fluorescence correlation spectroscopy (2P-FCS) within single dendritic spines of living hippocampal pyramidal neurons was used to resolve various subpopulations of mobile F-actin during activity-dependent structural changes such as potentiation induced spine head growth. Two major classes of mobile F-actin were discovered: very dynamic and about a hundred times less dynamic F-actin. Spine head enlargement upon application of Tetraethylammonium (TEA), a protocol previously used for the chemical induction of long-term potentiation (cLTP) strictly correlated to changes in the dynamics and filament numbers in the different actin filament fractions. Our observations suggest that spine enlargement is governed by a mechanism in which longer filaments are first cut into smaller filaments that cooperate with the second, increasingly dynamic shorter actin filament population to quickly reorganize and expand the actin cytoskeleton within the spine head. This process would allow a fast and efficient spine head enlargement using a major fraction of the actin filament population that was already present before spine head growth.

Neutralization of Nogo-A enhances synaptic plasticity in the rodent motor cortex and improves motor learning in vivo.

The membrane protein Nogo-A is known as an inhibitor of axonal outgrowth and regeneration in the CNS. However, its physiological functions in the normal adult CNS remain incompletely understood. Here, we investigated the role of Nogo-A in cortical synaptic plasticity and motor learning in the uninjured adult rodent motor cortex. Nogo-A and its receptor NgR1 are present at cortical synapses. Acute treatment of slices with function-blocking antibodies (Abs) against Nogo-A or against NgR1 increased long-term potentiation (LTP) induced by stimulation of layer 2/3 horizontal fibers. Furthermore, anti-Nogo-A Ab treatment increased LTP saturation levels, whereas long-term depression remained unchanged, thus leading to an enlarged synaptic modification range. In vivo, intrathecal application of Nogo-A-blocking Abs resulted in a higher dendritic spine density at cortical pyramidal neurons due to an increase in spine formation as revealed by in vivo two-photon microscopy. To investigate whether these changes in synaptic plasticity correlate with motor learning, we trained rats to learn a skilled forelimb-reaching task while receiving anti-Nogo-A Abs. Learning of this cortically controlled precision movement was improved upon anti-Nogo-A Ab treatment. Our results identify Nogo-A as an influential molecular modulator of synaptic plasticity and as a regulator for learning of skilled movements in the motor cortex.

The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity.

The fine tuning of neural networks during development and learning relies upon both functional and structural plastic processes. Changes in the number as well as in the size and shape of dendritic spines are associated to long-term activity-dependent synaptic plasticity. However, the molecular mechanisms translating functional into structural changes are still largely unknown. In this context, neurotrophins, like Brain-Derived Neurotrophic Factor (BDNF), are among promising candidates. Specifically BDNF-TrkB receptor signaling is crucial for activity-dependent strengthening of synapses in different brain regions. BDNF application has been shown to positively modulate dendritic and spine architecture in cortical and hippocampal neurons as well as structural plasticity in vitro. However, a global BDNF deprivation throughout the central nervous system (CNS) resulted in very mild structural alterations of dendritic spines, questioning the relevance of the endogenous BDNF signaling in modulating the development and the mature structure of neurons in vivo. Here we show that a loss-of-function approach, blocking BDNF results in a significant reduction in dendritic spine density, associated with an increase in spine length and a decrease in head width. These changes are associated with a decrease in F-actin levels within spine heads. On the other hand, a gain-of-function approach, applying exogenous BDNF, could not reproduce the increase in spine density or the changes in spine morphology previously described. Taken together, we show here that the effects exerted by BDNF on the dendritic architecture of hippocampal neurons are dependent on the neuron's maturation stage. Indeed, in mature hippocampal neurons in vitro as shown in vivo BDNF is specifically required for the activity-dependent maintenance of the mature spine phenotype.

Fluorescence nanoscopy by polarization modulation and polarization angle narrowing.

When excited with rotating linear polarized light, differently oriented fluorescent dyes emit periodic signals peaking at different times. We show that measurement of the average orientation of fluorescent dyes attached to rigid sample structures mapped to regularly defined (50 nm)(2) image nanoareas can provide subdiffraction resolution (super resolution by polarization demodulation, SPoD). Because the polarization angle range for effective excitation of an oriented molecule is rather broad and unspecific, we narrowed this range by simultaneous irradiation with a second, de-excitation, beam possessing a polarization perpendicular to the excitation beam (excitation polarization angle narrowing, ExPAN). This shortened the periodic emission flashes, allowing better discrimination between molecules or nanoareas. Our method requires neither the generation of nanometric interference structures nor the use of switchable or blinking fluorescent probes. We applied the method to standard wide-field microscopy with camera detection and to two-photon scanning microscopy, imaging the fine structural details of neuronal spines.

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. Whereas CA1 neurons from APLP1-KO or APLP2-KO mice showed normal neuronal morphology and spine density, APP-KO mice revealed a highly reduced dendritic complexity in mid-apical dendrites. Despite unaltered morphology of APLP2-KO neurons, combined APP/APLP2-DKO mutants showed an additional branching defect in proximal apical dendrites, indicating redundancy and a combined function of APP and APLP2 for dendritic architecture. Remarkably, APP-KO neurons showed a pronounced decrease in spine density and reductions in the number of mushroom spines. No further decrease in spine density, however, was detectable in APP/APLP2-DKO mice. Mechanistically, using APPsα-KI mice lacking transmembrane APP and expressing solely the secreted APPsα fragment we demonstrate that APPsα expression alone is sufficient to prevent the defects in spine density observed in APP-KO mice. Collectively, these studies reveal a combined role of APP and APLP2 for dendritic architecture and a unique function of secreted APPs for spine density.