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Principal Investigator: WEN-CHENG XIONG
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2024
Award: $643,654
Funding agency: National Institute on Aging
Alzheimer's disease (AD) is the most common form of dementia, affecting ~10% of the
population over 65 years of age. AD is a systemic disorder that affects the brain and
peripheral tissues. Patients with AD suffer from declined memory, cognitive deficits, and
changes in personality. In addition, AD is often associated with reduced muscle strength,
even at early stages. In some AD patients, muscle strength is reduced without loss of
muscle mass. However, pathological mechanisms of reduced muscle strength are not well
understood. Muscle contraction requires the efficient neurotransmission at the
neuromuscular junction (NMJ), a synapse between motor nerve terminals and skeletal
muscle fibers. Its formation requires a proteoglycan from motor nerves, agrin, which binds
to LRP4 to activate the receptor tyrosine kinase MuSK. We and others showed recently that
agrin signaling is also necessary for NMJ maintenance and is compromised in
neuromuscular disorders and in aged mice. Interestingly, APP, a risk gene of AD, is
expressed in skeletal muscles and becomes progressively concentrated at the NMJ after
birth. APP and its homolog APP-like protein 2 (APLP2) regulate NMJ formation. APP can
interact with LRP4 to promote agrin-induced AChR clustering. To understand pathological
mechanisms of muscle weakness in AD, we generated HSA-APPswe that specifically
express in muscles mutant APP with Swedish mutations (APPswe). Remarkably, HSA-
APPswe mice were weak in muscle contractile force, in particular that by nerve
stimulation, and NMJs became denervated with compromised neuromuscular transmission.
Initial mechanistic studies revealed diminished agrin signaling and increased cellular
senescence, a process originally defined as cell growth arrest but increasingly implicated in
ageing-associated processes. While these findings are exciting, they raise many questions.
Is muscle weakness in HSA-APPswe mice due to NMJ decline or vice versa? What is the
primary target of APPswe, pre- or post-synaptic function? How does APPswe impair the
NMJ, by diminishing agrin signaling or by enhancing cellular senescence, or both? And,
how? These questions will be addressed in this proposal. The overarching hypothesis at test
is that APPswe causes NMJ decline in aged mice by impairing agrin signaling and causing
cellular senescence in the muscle. To test this innovative hypothesis, we will determine
whether APPswe promotes NMJ decline by impairing agrin-LRP4 signaling and by
increasing muscle cell senescence. Results will uncover new pathological mechanisms by
which AD-association APP mutations damage the NMJ and reduce muscle strength and
reveal whether restoring agrin-LRP4 signaling and/or inhibiting cellular senescence prevent
NMJ decline and thus improve muscle strength. Such knowledge is prerequisite to
development of effective therapeutic interventions for muscle weakness in AD patients.
Terms: <(TNF)-α><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AD dementia><Address><Affect><Age Years><Aged 65 and Over><Aging><Agrin><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's disease patient><Alzheimer's patient><Alzheimers Dementia><Amentia><Amyloid A4 Protein Precursor><Amyloid Protein Precursor><Amyloid beta-Protein Precursor><Amyloid β-Protein Precursor><Apo E Receptor><ApoE Receptor><Apolipoprotein E Receptor><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Binding><Birth><Body Tissues><Brain><Brain Nervous System><Cachectin><Cell Aging><Cell Communication and Signaling><Cell Senescence><Cell Signaling><Cellular Aging><Cellular Expansion><Cellular Growth><Cellular Senescence><Cognitive deficits><Dementia><Development><Disease><Disorder><Encephalon><GeneHomolog><Genetic Alteration><Genetic Change><Genetic defect><HPGF><Hepatocyte-Stimulating Factor><Homolog><Homologous Gene><Homologue><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Impairment><Induced DNA Alteration><Induced Mutation><Induced Sequence Alteration><Interleukin-6><Intracellular Communication and Signaling><KM670/671/NL><KM670/671NL><Knowledge><LDL-Receptor Related Protein 1><Lipoprotein Receptor><Low Density Lipoprotein Receptor-Related Protein><Low-Density-Lipoprotein Receptor-Related Protein-1><MGI-2><MUSK gene><Macrophage-Derived TNF><Maintenance><Memory Loss><Mice><Mice Mammals><Molecular Interaction><Monocyte-Derived TNF><Motor><Mouse Homolog of Receptor Tyrosine Kinase NSK2><Murine><Mus><Muscle><Muscle Atrophy><Muscle Cell Contraction><Muscle Cells><Muscle Contraction><Muscle Fibers><Muscle Tissue><Muscle Weakness><Muscle, Skeletal, Receptor Tyrosine Kinase><Muscle-Specific Kinase><Muscular Atrophy><Muscular Contraction><Muscular Weakness><Mutation><Myeloid Differentiation-Inducing Protein><Myocytes><Myoneural Junction><Myotubes><NSK2><Nerve><Nerve Impulse Transmission><Nerve Transmission><Neuromuscular Diseases><Neuromuscular Junction><Neuronal Transmission><Parturition><Pathologic><Peripheral><Personality><Phenotype><Plasmacytoma Growth Factor><Population><Primary Senile Degenerative Dementia><Process><Proteins><Proteoglycan><Receptor Tyrosine Kinase MuSK><Replicative Senescence><Research><Rhabdomyocyte><Risk><Risk-associated variant><Signal Transduction><Signal Transduction Systems><Signaling><Skeletal Fiber><Skeletal Muscle><Skeletal Muscle Cell><Skeletal Muscle Fiber><Skeletal Myocytes><Swedish mutation><Synapses><Synaptic><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Testing><Therapeutic Intervention><Time><Tissues><Transmission><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Voluntary Muscle><aberrant aging><abnormal aging><above age 65><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age of 65 years onward><aged 65 and greater><aged 65+><aged mice><aged mouse><aged muscle><aged ≥65><aging associated><aging of muscle><aging related><alpha-2-Macroglobulin Receptor><alpha2-Macroglobulin Signaling Receptor><amyloid precursor protein><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><cell growth><cognitive defects><decreased muscle strength><developmental><dynapenia><dysfunctional age related change><dysfunctional aging><elderly mice><experiment><experimental research><experimental study><experiments><genome mutation><glia signaling><glial signaling><human old age (65+)><impaired aging><improved><innovate><innovation><innovative><interferon beta 2><intervention therapy><low muscle strength><maladaptive aging><memory decline><mild cognitive disorder><mild cognitive impairment><muscle aging><muscle breakdown><muscle bulk><muscle degradation><muscle deterioration><muscle form><muscle loss><muscle mass><muscle strength><muscle strength decline><muscle wasting><muscular><mutant><myoneural disorder><nerve signaling><neural signaling><neuromuscular degenerative disorder><neuromuscular disorder><neuromuscular transmission><neuronal signaling><neurotransmission><old age><old mice><over 65 years><pathological age related changes><pathological aging><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><postsynaptic><presynaptic><prevent><preventing><primary degenerative dementia><reduced muscle strength><risk allele><risk gene><risk genotype><risk loci><risk locus><risk variant><senescence><senescent><senile dementia of the Alzheimer type><synapse><synapse function><synaptic function><therapeutically effective><transmission process><≥65 years>