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Principal Investigator: Helen E Scharfman
Organization: NATHAN S. KLINE INSTITUTE FOR PSYCH RES
Fiscal Year: 2020
Award: $404,250
Funding agency: National Institute on Aging
ABSTRACT
It has been suggested that neuronal hyperexcitability is an important characteristic in Alzheimer’s
disease (AD) because it contributes to the impairment in memory and increasing levels of amyloid
β (Aβ) that characterize the disease. Using animal models of AD neuropathology we suggest that the
most common form of hyperexcitability is a synchronized spike in hippocampus and cortical neurons
that is similar to the spikes between seizures in epilepsy, called interictal spikes (IIS). Our data
suggests that IIS occur very early and are very common, yet seizures are rare. Therefore we have a
potential opportunity to characterize a novel biomarker, IIS, and clarify the relationship between
hyperexcitability and AD.
Preliminary data have primarily used a mouse model where the precursor to amyloid precursor
protein (APP), the precursor to Aβ is mutated to simulate a Swedish family with familial AD, and
expressed widely in the brain. By 5 weeks of age, months before Aβ deposition, we have found IIS as
the animals are sleeping. With age the animals develop frequent IIS that occur in other brain states
besides sleep and there are also memory impairments and plaque formation. In other animal models
IIS also occur, yet seizures are rare. When examining the brains of the young mice we find that the
basal forebrain (BF) cholinergic neurons and dentate gyrus granule cells show signs of elevated
activity, instead of hypoactivity that characterizes the brain at older ages. We suggest that BF
cholinergic neurons stimulate the granule cells and this leads to synchronized action potentials. In
support, the muscarinic cholinergic antagonist atropine reduces the IIS in sleep, as well as in vitro
measurements in hippocampal slices that we think reflect the abnormal activity. We now propose
experiments to test these hypotheses with multiple methods including viral-mediated silencing of
cholinergic neurons in vivo.
In the last part of the proposal we will examine two strategies that our pilot experiments show can
reduce IIS to determine if cognition and neuropathology are ameliorated. One of these has already
been tested in a mouse model of Down’s syndrome, a condition where AD is prevalent: maternal
choline supplementation. The second, a reduction of the neurotrophin receptor p75 (p75NTR), has
been tested in one of the mouse models we will use, the Tg2576 mouse, and it is already known that
it ameliorates memory impairments in the mice. In summary, this project will address an area of AD
research which has been difficult to clarify and controversial: hyperexcitability in AD. We suggest that
there are early signs of hyperexcitability, IIS, that present opportunities for better mechanistic
understanding and intervention.
Terms: <AD dementia><AD model><Abeta clearance><Acetylcholine Antagonists><Action Potentials><Address><Age><Age-Months><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease dementia><Alzheimer's disease model><Alzheimers Dementia><Alzheimers disease><Ammon Horn><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid β><Amyloid β clearance><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Animal Model><Animal Models and Related Studies><Animals><Antimuscarinic Agents><Area><Atropine><Axon><Aβ><Aβ clearance><Benign><Brain><Brain Nervous System><Cell Body><Cells><Characteristics><Cholinergic Antagonists><Cholinergic-Blocking Agents><Cholinolytics><Chronic><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Confusion><Confusional State><Cornu Ammonis><Data><Dentate Fascia><Deterioration><Disease><Disorder><Disturbance in cognition><Down Syndrome><Down's Syndrome><Downs Syndrome><Dysfunction><Electroencephalogram><Encephalon><Epilepsy><Epileptic Seizures><Epileptics><Event><FBJ Murine Osteosarcoma Viral Oncogene Homolog><FOS Family Protein><FOS Protein><Family><Fascia Dentata><Fast-Wave Sleep><Frequencies><Functional disorder><GP80-LNGFR><Generations><Genetic Alteration><Genetic Change><Genetic defect><Gyrus Dentatus><Hippocampus><Hippocampus (Brain)><Human><Hyperactive behavior><Hyperactivity><Hyperkinesia><Hyperkinesis><Hyperkinetic Movements><Impaired cognition><Impairment><In Vitro><Intervention><Intervention Strategies><Langdon Down syndrome><Life><Low-Affinity Nerve Growth Factor Receptor><Measurement><Medial><Mediating><Memory><Memory Deficit><Memory Loss><Memory impairment><Mental Confusion><Methods><Mice><Mice Mammals><Modeling><Modern Man><Mongolism><Motor Hyperactivity><Murine><Mus><Muscarinic Agents><Muscarinic Antagonists><Muscarinics><Mutate><Mutation><NGF Receptor><NGFR Protein><Nature><Neocortex><Nerve Cells><Nerve Growth Factor Receptor><Nerve Growth Factor Receptor p75><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neurons><Neurotropin Receptor p75><Paradoxical Sleep><Pathogenesis><Patients><Physiopathology><Population><Primary Senile Degenerative Dementia><Publishing><REM Sleep><Reaction><Research><Rhombencephalic Sleep><Role><Seizure Disorder><Seizures><Senile Plaques><Sleep><Slice><Testing><Tg2576><Transgenic Organisms><Trisomy 21><Ts65Dn><Viral><Work><a beta peptide><a-beta peptide clearance><abeta><abeta deposition><abeta peptide clearance><ages><alzheimer model><amyloid beta><amyloid beta clearance><amyloid beta deposition><amyloid beta peptide clearance><amyloid beta plaque><amyloid precursor protein><amyloid β deposition><amyloid-b plaque><amyloid-b protein><aβ deposition><aβ plaques><basal forebrain cholinergic neurons><base><beta amyloid fibril><c-fos Protein><choline supplementation><cholinergic neuron><chromosome 21 trisomy syndrome><cognitive dysfunction><cognitive loss><congenital acromicria syndrome><cored plaque><dementia of the Alzheimer type><dentate gyrus><diffuse plaque><dl-Hyoscyamine><dreaming sleep><early biomarkers><early detection biomarkers><early detection markers><epilepsia><epileptiform><epileptogenic><experiment><experimental research><experimental study><familial Alzheimer><familial Alzheimer disease><genome mutation><gp75 NGFR><granule cell><hippocampal><homotypical cortex><hyper-phosphorylated tau><hyperphosphorylated tau><improved><in vivo><interventional strategy><isocortex><memory consolidation><memory decline><memory dysfunction><mild cognitive disorder><mild cognitive impairment><model of animal><model organism><morbus Down><mouse Ts65Dn><mouse model><murine model><neopallium><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuronal><neuropathology><new marker><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel biomarker><novel marker><novel therapeutic approach><novel therapeutic intervention><novel therapy approach><overexpress><overexpression><p75 neurotrophin receptor><p75NTR><pathophysiology><potential biological marker><potential biomarker><primary degenerative dementia><protein expression><pseudohypertrophic progressive muscular dystrophy><rapid eye movement sleep><response><senile dementia of the Alzheimer type><septohippocampal><sleep epilepsy><social role><soluble amyloid precursor protein><success><supplementation with choline><tangle><transgenic><trisomy 21 syndrome>