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Principal Investigator: BRUCE A. BERKOWITZ
Organization: WAYNE STATE UNIVERSITY
Fiscal Year: 2024
Award: $1,086,200
Funding agency: National Institute on Aging
Therapeutically delaying the progressive decline in cognition in patients with Alzheimer’s
disease (AD) would transform AD into a manageable morbidity, a goal that has not been
achieved using drugs targeted to β-amyloid (Aβ) plaque deposition. Accumulating results
indicate that cognitive loss (linked to circuit / synaptic dysfunction) and β-amyloid (Aβ) plaque
deposition can occur independent of each other, with both driven by a cross-linked soluble
amyloid β-peptide oligomer - neuronal hyperactivity “AD cycle”. Remarkably, the prediction that
cognitive dysfunction can be restored without altering plaque deposition has been confirmed in
several AD models, for example, by drugs that prolong the opening time of the endoplasmic
reticulum (ER) ryanodine receptor type 2 (RyR2) calcium channel and suppress neuronal
hyperactivity.
Conventional biomarkers are unable to interrogate either part of the “AD cycle” in patients at
cellular resolution, an unmet goal for evaluating treatment efficacy at the prodromal stage. Here,
we propose a novel solution to this problem based on the retina, a readily accessible part of the
nervous system with damage similar to that found in the brain of patients with AD. The retina
develops soluble amyloid β-peptide oligomers and plaque deposition before their appearance in
the brain, as well as phosphorylated tau and neurofibrillary tangles. Before overt AD pathology
and cognitive decline are evident, patients report impaired contrast sensitivity (CS), a major risk
factor for falls as well as decreased survival. CS is driven by photoreceptors.
Our first-in-kind preliminary results in an AD model when there is sparse plaque deposition in
the retina show early impairment of CS, and rod hyperactivity measured using three OCT
mitochondria-driven biomarkers developed in our laboratory. We have also discovered that CS
impairment and rod hyperactivity biomarkers in 5xFAD male C57BL6/J (B6J) mice occur faster
than in 5xFAD male C57BL/6Tac (B6NTac) mice. In WT male B6J mice, rods showed a lower
OCT energy signature than in age-matched WT male B6NTac mice, indicating strain differences
in baseline mitochondria activity.
We propose to test two working hypotheses with three Specific Aims. First, that impaired CS,
a hyperactive rod energy signature, and/or synaptic dysfunction occur earlier B6J 5xFAD mice
than in B6NTac 5xFAD mice. Second that in 5xFAD mice, RyR2-targeted treatments that delay
cognitive declines mitigate changes in early CS and energy biomarkers, declines in rod synaptic
activity, and later spatial memory deficits but do not change the rate of plaque deposition.
Terms: <AD dementia><AD model><AD pathology><Abscission><Age><Aging><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer risk factor><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 disease patient><Alzheimer's disease risk><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Amentia><Ammon Horn><Amyloid (Aβ) plaques><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Appearance><Assay><Aβ><Bioassay><Biological Assay><Biological Markers><Brain><Brain Nervous System><Ca Release Channel-Ryanodine Receptor><Calcium Channel><Calcium Channel Antagonist Receptor><Calcium Channel Blocker Receptors><Calcium Ion Channels><Calcium-Ryanodine Receptor Complex><Coenzyme Q-Cytochrome-c Reductase><Coenzyme QH2-Cytochrome-c Reductase><Cognition><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex III><Contrast Sensitivity><Cornu Ammonis><Cytochrome b-c2 Oxidoreductase><Dementia><Deposit><Deposition><Dihydroubiquinone-Cytochrome-c Reductase><Disease><Disorder><Disturbance in cognition><Doppler OCT><Drug Targeting><Drug usage><Drugs><Dysfunction><Electron Transport Complex III><Encephalon><Endoplasmic Reticulum><Ergastoplasm><Evaluation><Excision><Extirpation><Female><Functional disorder><Glutamates><Goals><Hippocampus><Hydrogen Oxide><Hyperactivity><Impaired cognition><Impairment><In Situ><Individual><L-Glutamate><Laboratories><Learning><Left><Light><Link><Measures><Medication><Memory Deficit><Memory Loss><Memory impairment><Methods><Mice><Mice Mammals><Mitochondria><Morbidity><Morbidity - disease rate><Murine><Mus><Names><Nerve Cells><Nerve Unit><Nervous System><Neural Cell><Neuritic Plaques><Neurocyte><Neurofibrillary Tangles><Neurologic Body System><Neurologic Organ System><Neurons><OCT Tomography><Optical Coherence Tomography><Patients><Pharmaceutical Preparations><Photoradiation><Photoreceptor Cell><Photoreceptors><Photosensitive Cell><Physiopathology><Prediction of Response to Therapy><Primary Senile Degenerative Dementia><Proxy><Public Health><QH(2)-Cytochrome-c Reductase><QH(2)-Ferricytochrome-c Oxidoreductase><Removal><Reporting><Research><Resolution><Retina><Risk Factors><Rod><Ryanodine Receptor><Ryanodine Receptor Calcium Release Channel><Senile Plaques><Surgical Removal><Synapses><Synaptic><Testing><Text><Therapeutic><Time><Treatment Efficacy><Ubihydroquinone-Cytochrome-c Reductase><Ubiquinol-Cytochrome-c Reductase><Ubiquinol-ferricytochrome-c oxidoreductase><Ubiquinone-Cytochrome b-c2 Oxidoreductase><VDCC><Visual Contrast Sensitivity><Visual Receptor><Voltage-Dependent Calcium Channels><Water><Whole-Cell Recordings><Wild Type Mouse><a beta peptide><abeta><ages><alzheimer model><alzheimer risk><amyloid beta><amyloid beta plaque><amyloid-b plaque><amyloid-b protein><aβ plaques><beta amyloid fibril><bio-markers><biologic marker><biomarker><biomarker driven><biomarker signature><cognitive dysfunction><cognitive loss><cored plaque><crosslink><diffuse plaque><drug use><drug/agent><experience><falls><glutamatergic><hippocampal><imaging biomarker><imaging marker><imaging-based biological marker><imaging-based biomarker><imaging-based marker><indexing><intervention efficacy><male><memory decline><memory dysfunction><mild cognitive disorder><mild cognitive impairment><mitochondrial><name><named><naming><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neuronal><novel><optical Doppler tomography><optical coherence Doppler tomography><p-tau><p-τ><pathophysiology><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><phospho-tau><phospho-τ><phosphorylated tau><post-translational modification of tau><posttranslational modification of tau><predict therapeutic response><predict therapy response><prevent><preventing><primary degenerative dementia><rate of change><resection><resolutions><response><retina imaging><retinal imaging><senile dementia of the Alzheimer type><soluble amyloid precursor protein><spatial memory><synapse><tangle><tau phosphorylation><tau posttranslational modification><tau-1><therapeutic efficacy><therapy efficacy><therapy prediction><treatment prediction><treatment response prediction><wildtype mouse><τ phosphorylation>