Adhesion molecule L1 binds to amyloid beta and reduces Alzheimer's disease pathology in mice
Introduction
Alzheimer's disease (AD) is the most common cause of dementia in elderly individuals. In AD patients brain regions involved in learning, memory and emotions are reduced in size due to neuronal cell death, astrogliosis and synaptic degeneration (Albert, 2011, Hardy, 2006, Jucker and Walker, 2011, Mattson, 2004). Pathological hallmarks of AD are intracellular neurofibrillary tangles and extracellular aggregates composed of amyloid beta peptides (Aβ) (Ittner and Götz, 2011). Treatments restoring neuronal function and keeping AD pathology at bay are therefore of prime importance. Beneficial adhesion molecules that prevent neuronal cell death and spare imperiled synapses represent potential venues for treatment. The neural cell adhesion molecule L1 is one of such molecules and has attracted our attention in the context of AD, since elevated levels of L1 were detected in the cerebrospinal fluid of patients with AD, vascular dementia and dementia of mixed type (Strekalova et al., 2006). We hypothesized that L1 may beneficially influence the adverse symptoms in an animal model of AD, because L1 has improved the negative symptoms in several animal models of acute and chronic neurological disorders: Infusion of L1 into the injured spinal cord of rats promoted regeneration (Roonprapunt et al., 2003) and L1-transfected embryonic stem cells as well as Schwann cells improved regeneration after spinal cord injury in mice (Chen et al., 2005, Lavdas et al., 2009); expression of L1 in the spinal cord injured mouse via adeno-associated-virus (AAV) resulted in improved locomotor recovery, regrowth/sprouting and sparing of severed axons, and reduced reactive astrogliosis, by limiting astrocyte proliferation and migration, when injected both acutely and in a sub-chronic phase of injury (Chen et al., 2007, Lee et al., 2012); in a mouse model of Parkinson's disease, embryonic stem cell-derived L1 overexpressing neural aggregates enhanced survival and migration of transplanted cells, differentiation into dopaminergic neurons, survival of endogenous dopaminergic neurons and behavioral recovery (Cui et al., 2010); neural stem cells expressing L1 upon differentiation into astrocytes promoted host–donor cell interactions when transplanted in a mouse model of Parkinson's disease (Ourednik et al., 2009); in a mouse model of Huntington's disease, transplanted L1 overexpressing embryonic stem cells showed preferential neuronal over glial cell differentiation, increased yield of γ-aminobutyric acid (GABA)-ergic neurons, concomitant with behavioral improvement (Bernreuther et al., 2006). Noteworthy in the context of AD is the observation that L1 increases the levels of choline acetyltransferase in the developing and injured central nervous system (Cui et al., 2011a, Lee et al., 2012).
To further explore the therapeutic potential of L1 in neurodegenerative disorders, we used a mouse model for AD with accelerated progression of disease symptoms: the transgenic mouse APPPS1 (Gengler et al., 2010, Radde et al., 2006) which carries the KM670/671NL mutated (“Swedish mutation”) human amyloid precursor protein (APP) and the L166P mutated human presenilin-1 (PS-1). This mouse shows many histological aspects of cerebral amyloidosis, including plaque formation, dystrophic synaptic boutons, hyperphosphorylated tau-positive neuritic structures, astrogliosis and increased numbers of microglia when compared to wild-type mice of the same C57BL/6J inbred genetic background.
In the present study, we injected AAV-L1 or AAV-green fluorescent protein (GFP) as a negative control into the hippocampus and occipital cortex of APPPS1 mice at three months of age, when the first histological abnormalities become apparent. When analyzed four months after injection of virus, overexpression of L1 in neurons and glia led to a reduction of plaque load, astrogliosis and reduced loss of perisomatic inhibitory synapses in the CA1 and CA3 regions of the hippocampus. Direct and specific binding of the extracellular domain of L1 – but not of CHL1, the close homolog of L1 – to Aβ42 reduced aggregation in vitro. Our results indicate that L1 ameliorates the histopathology of AD in a mouse model, probably by directly interacting with Aβ, thus raising the hope that it may become a promising candidate for therapy of AD in humans.
Section snippets
Animals
Three-month-old transgenic male APPPS1 (C57BL/6J-TgN; Thy1-APPKM670/671NL; Thy1-PS1L166P) mice were obtained from a breeding colony at the University of Tübingen, Germany. These mice co-express mutated human APP (Swedish double mutation) and mutated presenilin-1 under the neuron-specific murine Thy-1 promoter element on the C57BL/6J background (Radde et al., 2006). The wild-type C57BL/6J mice were obtained from the breeding colony at the central animal facility of the Universitätsklinikum
AAV-mediated transduction of the occipital cortex and hippocampus
To deliver L1 into the brain, we used AAV serotype 5, which was designed to drive L1 expression under the control of the murine cytomegalovirus immediately early promoter and which has been successfully used to overexpress L1 after spinal cord injury in mice (Chen et al., 2007, Lee et al., 2012). Immunoblot analysis of homogenates of AAV-L1 injected and corresponding non-injected contralateral control hemispheres showed an increase of approximately 20% in the level of L1 expression in the
Discussion
In this study we present evidence that AAV-mediated overexpression of L1 in neurons and astrocytes confers beneficial effects in a mouse model of AD. AD has an intricate and not yet fully understood pathology that would demand a complex therapeutic approach (Herrup, 2010). The positive effects of L1 overexpression in an AD mouse model include the reduction of amyloid plaque load, decreased astrogliosis and better preservation of inhibitory synaptic terminals on pyramidal cell bodies in the
Acknowledgments
We are grateful to Emanuela Szpotowicz for excellent technical assistance, to Isabelle Aubert, Andrey Irintchev, Carsten Schmidt for critical reading of the manuscript, and Southeast Europe Cooperation Hamburg for support. We thank Mathias Jucker for the generous gift of APPPS1 mice. Authors declare no conflict of interest. This work was supported by grants from the New Jersey Commission for Spinal Cord Research and Li Ka-Shing Foundation (to M.S.).
References (60)
Changes in cognition
Neurobiol Aging
(2011)- et al.
Label-free assays on the BIND system
J. Biomol. Screen.
(2004) - et al.
The soluble form of the cancer-associated L1 cell adhesion molecule is a pro-angiogenic factor
Int. J. Biochem. Cell Biol.
(2009) - et al.
Adhesion molecule L1 overexpressed under the control of the neuronal Thy-1 promoter improves myelination after peripheral nerve injury in adult mice
Exp. Neurol.
(2011) A hundred years of Alzheimer's disease research
Neuron
(2006)- et al.
Expression of the neural adhesion molecule L1 in the deafferented dentate gyrus
Neuroscience
(1996) - et al.
CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease
Neurobiol. Aging
(2013) - et al.
Generation and nuclear translocation of a sumoylated transmembrane fragment of the cell adhesion molecule L1
J. Biol. Chem.
(2012) - et al.
Polysialic acid glycomimetic promotes functional recovery and plasticity after spinal cord injury in mice
Mol. Ther.
(2010) - et al.
Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease
Neurobiol. Aging
(2004)
Reduced GABAergic transmission and number of hippocampal perisomatic inhibitory synapses in juvenile mice deficient in the neural cell adhesion molecule L1
Mol. Cell. Neurosci.
MRC Cognitive Function and Ageing Neuropathology Study Group. Astrocyte phenotype in relation to Alzheimer-type pathology in the ageing brain
Neurobiol. Aging
Elevated levels of neural recognition molecule L1 in the cerebrospinal fluid of patients with Alzheimer disease and other dementia syndromes
Neurobiol. Aging
Clearance of amyloid-beta in Alzheimer's disease: progress, problems and perspectives
Drug Discov. Today
Cell cycle activation and spinal cord injury
Neurotherapeutics
The neural cell adhesion molecules L1 and CHL1 are cleaved by BACE1 protease in vivo
J. Biol. Chem.
Amyloid-beta aggregates cause alterations of astrocytic metabolic phenotype: impact on neuronal viability
J. Neurosci.
Several extracellular domains of the neural cell adhesion molecule L1 are involved in neurite outgrowth and cell body adhesion
J. Neurosci.
Identification of the border between fibronectin type III homologous repeats 2 and 3 of the neural cell adhesion molecule L1 as a neurite outgrowth promoting and signal transducing domain
J. Neurobiol.
Neural cell adhesion molecule L1-transfected embryonic stem cells promote functional recovery after excitotoxic lesion of the mouse striatum
J. Neurosci.
Dynamics of the microglial/amyloid interaction indicate a role in plaque maintenance
J. Neurosci.
Prevention of neuronal cell death by neural adhesion molecules L1 and CHL1
J. Neurobiol.
Cell adhesion molecule L1-transfected embryonic stem cells with enhanced survival support regrowth of corticospinal tract axons in mice after spinal cord injury
J. Neurotrauma
Adeno-associated virus-mediated L1 expression promotes functional recovery after spinal cord injury
Brain
Optical biosensors in drug discovery
Nat. Rev. Drug Discov.
Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery in Parkinsonian mice
Brain
The cell adhesion molecule L1 regulates the expression of choline acetyltransferase and the development of septal cholinergic neurons
Brain Behav.
Embryonic stem cell-derived L1 overexpressing neural aggregates enhance recovery after spinal cord injury in mice
PLoS One
A new role for the cell adhesion molecule L1 in neural precursor cell proliferation, differentiation, and transmitter-specific subtype generation
J. Neurosci.
The Mouse Brain in Stereotaxic Coordinates
Cited by (45)
Effects of L1 adhesion molecule agonistic mimetics on signal transduction in neuronal functions
2023, Biochemical and Biophysical Research CommunicationsCitation Excerpt :NIH Clinical Collection 1 Library (446 compounds; http://www.nihclinicalcollection.com/; Evotec, San Francisco, CA); crotamiton ((E)-N-ethyl-N-(2-methylphenyl)but-2-enamide; CAS 124236-29-9), ethynyl estradiol ((17α-Ethynylestradiol; 17α-Ethynyl-1,3,5(10)-estratriene-3,17β-diol; 19-Nor-1,3,5(10),17α-pregnatrien-20-yne-3,17-diol); Cat#sc-205318; CAS 57-63-6), trimebutine ([2-(dimethylamino)-2-phenylbutyl] 3,4,5-trimethoxybenzoate Maleate; Cat#sc-204928; CAS 34140-59-5) were from Santa Cruz Biotechnology Inc (Santa Cruz, CA, USA); tacrine hydrochloride (1,2,3,4-tetrahydroacridin-9-amine; hydrochloride; Cat#0965/100; CAS 1684-40-8), honokiol (2-(4-hydroxy-3-prop-2-enylphenyl)-4-prop-2-enylphenol; Cat#4590/10; CAS 35354-74-6), and S-duloxetine hydrochloride ((3S)–N-methyl-3-naphthalen-1-yloxy-3-thiophen-2-ylpropan-1-amine; Cat#4798/10; CAS 136434-34-9) were from Tocris, Bristol, UK. Cerebellar granule neurons were prepared from 6- to 8-day-old mice as described [9]. In brief, the cerebellar cortices were cut into small pieces, digested with trypsin and DNase for 15 min, washed with Hank's balanced salt solution (HBSS), and centrifuged at 100×g for 15 min at 4 °C.
Inhibition of excessive kallikrein-8 improves neuroplasticity in Alzheimer's disease mouse model
2020, Experimental NeurologyCitation Excerpt :The KLK8 substrate NRG1 protects neurons from Aβ induced apoptosis and counteracts cognitive deficits and neuropathology in AD mice (Di Segni et al., 2005; Woo et al., 2012; Xu et al., 2016). L1-CAM has anti-aggregatory properties, reduces Aβ plaque load in AD mice (Djogo et al., 2013) and is cleaved not only by KLK8 but also by the β-site amyloid precursor protein-cleaving enzyme (BACE1), an enzyme required for Aβ production (Zhou et al., 2012). The KLK8 substrate fibronectin promotes secretion of the amyloid precursor protein (APP) and impedes APP integration into plasma membranes and subsequent Aβ biogenesis (Monning et al., 1995).
Role of the adhesion molecule F3/Contactin in synaptic plasticity and memory
2017, Molecular and Cellular NeuroscienceCitation Excerpt :AD brains also presented an alteration of NCAM and polysialylated NCAM (PSA-NCAM) expression that paralleled the disease severity (Mikkonen et al., 1999; Yew et al., 1999; Aisa et al., 2010), and an increase of NCAM and L1 has been found in CSF of AD patients (Yin et al., 2009: Strekalova et al., 2006). Interestingly, NCAM mimicking peptides seem to have a beneficial effect against the impairment of learning and memory (Foley et al., 2000; Cambon et al., 2003; Hartz et al., 2003; Cambon et al., 2004; Secher et al., 2006), and CAMs or their derivatives rescued AD-like pathology in animal models (Klementiev et al. 2007; Djogo et al. 2013). For this they have been used in clinical trials against cognitive impairment (Strekalova et al., 2006; Anand et al., 2007; Gnanapavan et al., 2010), strengthening the hypothesis that modulating CAMs signaling might represent a novel therapeutical approach for AD.
- 1
These authors contributed equally.