Document text
Principal Investigator: Tristan Shuman
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $124,813
Funding agency: National Institute on Aging
Project Summary/Abstract – From Parent Grant
Alzheimer's disease (AD) is a form of dementia characterized by memory loss and progressive cognitive
impairments. The leading hypotheses over the past decade have assumed that these symptoms are due to
accumulation of amyloid-beta (Aβ) and tau proteins that lead to neurodegeneration. However, treatments that
reduce Aβ levels have largely been ineffective in clinical trials and strategies to target tau have proven difficult.
Numerous failed drug trials have raised concerns that reducing pathological proteins without preventing or
reversing functional changes in the affected cells and networks may be insufficient for treatment. This highlights
a need to examine how AD pathology impacts brain regions, connections, and activity patterns that are important
for memory. By investigating specific circuits that are known to be vulnerable early in disease progression, we
can gain valuable insight into the initial network changes underlying progressive cognitive decline and identify
possible targets for early therapeutic interventions. Given the strong evidence for dysfunction in hippocampal
processing and spatial memory in AD, it is critical to understand whether these changes are driven by abnormal
inputs or local hippocampal changes. The medial entorhinal cortex (MEC) provides critical spatial inputs to the
hippocampus and its vulnerability in early AD is well established. Therefore, this proposal will test the hypothesis
that changes in MEC function emerge prior to cognitive decline and hippocampal processing deficits, and provide
an early point of circuit dysfunction that could drive development of memory impairments. In Aim 1, we will first
use in vitro electrophysiology to characterize how intrinsic properties of distinct cell types in MEC and CA1 are
altered during the progression of memory impairments. In Aim 2, we will use silicon probes to simultaneously
record from 512 channels throughout MEC and hippocampus to determine how and when synchrony of single
units and local field potentials (LFPs) within and across regions breaks down in models of AD pathology. In Aim
3, we will use in vivo calcium imaging with miniature microscopes to track the development of spatial coding
deficits across months in MECII, MECIII, and CA1 neurons as mice run on a linear track and explore an open
field. Specialized viral targeting tools will allow us to isolate specific MEC subpopulations and test the hypothesis
that MECII stellate cells exhibit altered spatial coding prior to deficits in CA1. These experiments will use 3 distinct
mouse models of AD pathology and neurodegeneration covering Aβ (APP-KI), tau (P301S), and combinatorial
(3x-Tg) transgenes to identify convergent mechanisms of circuit dysfunction across models. Together, these
aims will isolate specific circuits that break down to produce memory deficits in mouse models of AD pathology.
Terms: <AD dementia><AD model><AD pathology><Affect><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Aβ><Brain region><Cell Body><Cells><Clinical Trials><Code><Coding System><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Cornu Ammonis><Dementia><Development><Disease><Disease Progression><Disorder><Disturbance in cognition><Drugs><Dysfunction><Electrophysiology><Electrophysiology (science)><Entorhinal Area><Exhibits><Functional disorder><Hippocampus><Impaired cognition><In Vitro><In vivo two-photon calcium imaging><MT-bound tau><Medial><Medication><Memory><Memory Deficit><Memory Loss><Memory impairment><Mice><Mice Mammals><Microscope><Modeling><Murine><Mus><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurocyte><Neuron Degeneration><Neurons><Neurophysiology / Electrophysiology><Pathologic><Pathology><Pattern><Pharmaceutical Preparations><Physiopathology><Primary Senile Degenerative Dementia><Property><Proteins><Running><Si element><Silicon><Site><Symptoms><Testing><Therapeutic Intervention><Transgenes><Viral><a beta peptide><abeta><abeta accumulation><abeta aggregation><alzheimer model><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><aβ accumulation><aβ aggregation><beta amyloid fibril><cell type><cognitive defects><cognitive dysfunction><cognitive loss><combinatorial><developmental><drug/agent><electrophysiological><entorhinal cortex><experiment><experimental research><experimental study><experiments><hippocampal><in vivo calcium imaging><insight><intervention therapy><memory decline><memory dysfunction><microtubule bound tau><microtubule-bound tau><mouse model><murine model><neural degeneration><neurodegeneration><neurodegenerative><neurological degeneration><neuronal><neuronal degeneration><parent grant><pathophysiology><prevent><preventing><primary degenerative dementia><senile dementia of the Alzheimer type><soluble amyloid precursor protein><spatial memory><stellate cell><tau><tau Proteins><tau factor><tool><transgene><τ Proteins>