APKC inhibitors and methods of treating a neurodegenerative disease or disorder
Inventors
Farese, Robert Vito • Sajan, Mini Paliyath • HIGGS, MARGARET GENEVIEVE
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-11865125-B2
Publication Date
2024-01-09
Expiration Date
2037-03-24
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Abstract
Provided herein are formulations effective for and methods of treating or preventing a neurodegenerative disorder in a subject in need thereof that can include administering an amount of an aPKC inhibitor to a subject in need thereof.
Core Innovation
The present disclosure provides formulations and methods for treating or preventing neurodegenerative disorders, such as Alzheimer's disease (AD), by administering an amount of an atypical protein kinase C (aPKC) inhibitor to a subject in need thereof. The aPKC inhibitor can be capable of crossing the blood brain barrier to directly inhibit aPKC in the central nervous system (CNS) or may not cross it but indirectly reduce CNS aPKC activity by lowering systemic hyperinsulinemia through peripheral actions, such as in the liver.
The problem addressed is the limited therapies and lack of cures for Alzheimer's disease and other neurodegenerative disorders, which constitute a significant public health burden. Although insulin resistance has been implicated, the brain itself may not be insulin resistant but rather hyperinsulinized, leading to aberrant signaling involving elevated aPKC and Akt activities that contribute to AD pathologies including increased β-secretase activity, Aβ1-40/42 peptide accumulation, and tau phosphorylation.
The innovation relates to the discovery that inhibition of aPKC, either directly in the brain using inhibitors capable of crossing the blood brain barrier such as ICAPP and ACPD, or indirectly via liver-selective inhibitors such as aurothiomalate (ATM) that reduce systemic hyperinsulinemia, can restore normal CNS signaling. This decrease in aPKC activity attenuates downstream pathological events implicated in AD, including reductions in β-secretase activity, Aβ1-40/42 peptide levels, and phospho-tau levels, and increases activity or levels of neuroprotective factors such as FoxO transcription factors and PGC-1α.
Claims Coverage
The patent contains one independent claim directed to a method of treating Alzheimer's disease with a specific aPKC inhibitor. Seven inventive features are described relating to the biochemical and clinical effects of this inhibitor.
Using aurothiomalate (ATM) for treating Alzheimer's disease
The method comprises administering an effective amount of aurothiomalate to a subject in need thereof for treating Alzheimer's disease or symptoms thereof.
Decreasing phosphorylation of Akt by administering ATM
The effective amount of ATM decreases phosphorylation of Akt in the subject.
Decreasing activity of aPKC using ATM
The administered ATM amount decreases activity of atypical protein kinase C (aPKC).
Reducing β-secretase activity with ATM
ATM administration effectively reduces the activity of β-secretase (BACE1) in the subject.
Reducing Aβ1-40/42 peptide levels by ATM
The amount of ATM is effective to decrease the amount of Aβ1-40/42 peptides associated with Alzheimer's pathology.
Reducing thr-231-phospho-tau levels by ATM
ATM administration decreases levels of threonine-231 phosphorylated tau protein in the subject.
Modulating activity of PKC-λ/ι and FoxO factors and PGC-1α with ATM
The administered amount of ATM decreases activity of 70 kDa PKC-λ/ι and increases activity of FoxO1, FoxO3a, or both, as well as increasing activity and/or levels of PGC-1α.
The claims focus on the therapeutic use of aurothiomalate to modulate multiple insulin signaling pathways implicated in Alzheimer's disease, including decreasing aPKC and Akt phosphorylation and activity, reducing β-secretase activity and pathological peptide levels, and upregulating protective transcription factors, demonstrating a multifaceted approach to AD treatment.
Stated Advantages
The aPKC inhibitors can restore normal brain insulin signaling altered by hyperinsulinemia.
They reduce Alzheimer's disease-associated pathologies including β-secretase activity, Aβ1-40/42 peptide accumulation, and phospho-tau levels.
Administration of aPKC inhibitors in animal models improves memory functions impaired by high fat feeding and insulin resistance.
Documented Applications
Treatment or prevention of neurodegenerative disorders, specifically Alzheimer's disease or symptoms thereof.
Use in subjects who are hyperinsulinemic, diabetic, obese, or have metabolic syndrome with the goal to modulate CNS insulin signaling abnormalities.
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