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Principal Investigator: Erin H. Norris
Organization: ROCKEFELLER UNIVERSITY
Fiscal Year: 2024
Award: $412,290
Funding agency: National Institute on Aging
PROJECT SUMMARY
Alzheimer's disease (AD) is a complex neurodegenerative disorder with multiple pathologies, such as
proteinaceous brain inclusions and neuroinflammation. The vascular system is also recognized as a
factor in AD, yet there are few models to study the mechanism. We and others have found that the Aβ
peptide, a known driver of AD, can activate the plasma contact system, which can lead to blood clot
formation and inflammation via generation of bradykinin upon cleavage of high molecular weight
kininogen (HK). There are three main lines of evidence that the contact system is involved in AD
pathology: 1) Aβ activates factor XII (F12), which initiates the contact system; 2) AD patient plasma
has increased contact system activation compared to that of age-matched, non-demented individuals;
and 3) Knockdown of the contact system using an anti-F12 antisense oligonucleotide ameliorates AD
pathology in a mouse model. HK circulates in blood as a complex with other coagulation factors, and
it serves as a non-enzymatic co-factor for the activation of these proteins. Compared to other
components of the contact system, depletion of HK offers more robust protection from blood clotting
and inflammation due to its central role in both pathways.
We have generated antibodies that are specific for cleaved HK that could help identify AD patients
with contact system involvement. We also have developed antibodies that block HK cleavage, which
might be beneficial to patients as they might ameliorate some of the pathologies of AD. It is important
to note that people who lack a contact system are not prone to bleeding, and therefore, blocking this
system in AD patients would not risk intracerebral hemorrhage.
Despite decades of research, there are no effective treatments that slow or prevent AD. Progress in
treating AD requires a multidisciplinary approach. We hypothesize that blocking the contact system
could reduce vascular and inflammatory pathologies in AD patients. We propose to further develop
our anti-HK antibodies for AD patient diagnostic and therapeutic use.
Terms: <AD dementia><AD diagnostic><AD pathology><Abbreviations><Activated Blood Coagulation Factor XII><Activated Factor XII><Age><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 diagnosis><Alzheimer's diagnostic><Alzheimer's disease diagnosis><Alzheimer's disease diagnostic><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's disease test><Alzheimer's pathology><Alzheimer's patient><Alzheimer's test><Alzheimers Dementia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Antibodies><Antisense Agent><Antisense Oligonucleotides><Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg><Assay><Aβ><Bioassay><Biological Assay><Bleeding><Blocking Antibodies><Blood><Blood Clotting><Blood Coagulation Factor><Blood Coagulation Factor XI><Blood Plasma><Blood Reticuloendothelial System><Blood Vessels><Blood coagulation><Bradykinin><Brain><Brain Nervous System><Cerebral Brain Hemorrhage><Cerebral Hemorrhage><Cerebral Parenchymal Hemorrhage><Cerebral hemisphere hemorrhage><Cerebrum Hemorrhage><Clinical><Clinical Treatment Moab><Clotting><Coagulation><Coagulation Factor XI><Coagulation Factor XIIa><Coagulation Factors><Coagulation Process><Cognitive Manifestations><Cognitive Symptoms><Complex><Degenerative Neurologic Disorders><Detection><Diagnostic><Diagnostic tests><EC 3.4.21.34><ELISA><Encephalon><Enzyme-Linked Immunosorbent Assay><Factor XI><Factor XIIa><Fitzgerald Factor><Generations><Goals><HMWK><Hemorrhage><High-Molecular-Weight Kininogen><Human><In vivo analysis><Individual><Inflammation><Inflammatory><Intracerebral Hemorrhage><Kallikrein 3><Kallikrein I><Mice><Mice Mammals><Modeling><Modern Man><Monoclonal Antibodies><Murine><Mus><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurobehavioral Manifestations><Neurobehavioral Signs and Symptoms><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic Degenerative Conditions><P-30 Antigen><Pathologic><Pathology><Pathway interactions><Patients><Peptides><Persons><Plasma><Plasma Kallikrein><Plasma Kallikrein Precursor><Plasma Prekallikrein><Plasma Serum><Plasma Thromboplastin Antecedent><Prekallikrein Activator><Primary Senile Degenerative Dementia><Prostate Specific Antigen Preproprotein><Prostate-Specific Antigen><Proteins><Research><Reticuloendothelial System, Serum, Plasma><Role><Sampling><Scheme><Semenogelase><Seminin><Serum Kallikrein><System><Testing><Therapeutic><Therapeutic Uses><Vascular Diseases><Vascular Disorder><Vascular System><a beta peptide><abeta><ages><amyloid beta><amyloid-b protein><antibody assay><antibody based test><antibody test><antihemophilic factor C><antisense oligo><arm><beta amyloid fibril><blood loss><blood vessel disorder><clotting factor><cofactor><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><effective therapy><effective treatment><enzyme linked immunoassay><gamma-Seminoprotein><hK3 Kallikrein><in vivo><in vivo evaluation><in vivo testing><inhibiting antibody><interdisciplinary approach><kallidin 9><kallidin I><knock-down><knockdown><mAbs><monoclonal Abs><mouse model><multidisciplinary approach><murine model><neural inflammation><neurobehavioral symptom><neurodegenerative illness><neuroinflammation><neuroinflammatory><non-demented><nondemented><pathway><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><prevent><preventing><primary degenerative dementia><protein activation><senile dementia of the Alzheimer type><social role><soluble amyloid precursor protein><test for Alzheimer><vascular><vascular dysfunction><vasculopathy>