APP-Specific CD8+ T Cell Assay for LOAD Diagnosis

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Solution Overview

Problem

Current mouse models for late-onset Alzheimer's disease (LOAD) fail to accurately mimic human pathology, particularly age-related factors, and do not effectively predict treatment success, as they lack features such as neuronal loss and neurofibrillary deposition, and CD8 T cell homeostatic expansion, which are relevant to AD pathology.

Innovation Solution

An assay is developed to determine the likelihood of LOAD by measuring the levels of amyloid precursor protein (APP)-specific CD8+ T cells in samples, using MHC multimers labeled with detection agents, and administering therapeutic agents such as APP peptide-specific MHC multimers conjugated to cytotoxic agents to treat subjects with elevated APP-specific CD8+ T cell levels.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If FAD-based mouse models are used to study AD pathology, then genetic mutations can be manipulated, but age-related factors and CD8 T cell homeostatic expansion are missing

Engineering Contradiction:

Improvemodel adaptability to human AD featuresVSAvoidpredictive value for treatment success

Core Design Contradiction:

Adaptability or versatilityVSReliability

Solution Approach 1:

The patent introduces CD8 T cell homeostatic expansion as an intermediary mechanism that bridges the gap between genetic AD models and human pathology. By inducing CD8 T cell expansion in mouse models, the system becomes a more accurate mediator of AD pathology, enabling better prediction of treatment outcomes while maintaining experimental control.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the mouse model by inducing CD8 T cell homeostatic expansion, which changes the immunological parameters of the model to better reflect human AD. This parameter change enables the model to exhibit age-related features such as neuronal loss and neurofibrillary deposition, improving its reliability for treatment prediction.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If CD8 T cell homeostatic expansion is induced in mouse models, then AD-like pathology improves, but model complexity increases

Engineering Contradiction:

Improveaccuracy of AD pathology mimicryVSAvoidmodel complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent segments the AD pathology into distinct components: CD8 T cell homeostatic expansion, neuronal loss, neurofibrillary deposition, and amyloid beta accumulation. By studying these segments separately and then combining them, the model achieves high accuracy in mimicking human AD without requiring all features to be present simultaneously in the base model.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent performs preliminary CD8 T cell expansion in young mice before inducing AD pathology. This preliminary action establishes the immunological foundation that enables subsequent development of AD-like features, allowing the model to achieve high reliability while maintaining manageable complexity through staged development.

Inventive Principle:

Principle #10Preliminary action

3Reliability

If APP-specific CD8+ T cells are targeted for treatment, then AD pathology can be addressed, but specificity and off-target effects must be managed

Engineering Contradiction:

Improvetreatment efficacyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies local quality by targeting specifically APP-specific CD8+ T cells rather than eliminating all CD8+ T cells. This selective targeting ensures treatment efficacy against AD pathology while preserving other beneficial immune functions, thereby reducing off-target effects and improving the safety profile of the therapy.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs feedback mechanisms to monitor and adjust CD8+ T cell targeting. By tracking the specific population of APP-reactive T cells and their activity, the treatment can be fine-tuned to maintain efficacy while minimizing harmful effects, allowing for adaptive management of the therapeutic intervention.

Inventive Principle:

Principle #23Feedback

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The assay effectively identifies subjects at risk for LOAD and provides a method for treatment by targeting APP-specific CD8+ T cells, which are associated with AD pathology, potentially addressing the limitations of existing mouse models and improving treatment prediction and efficacy.

Implementation Method 1

assaying the sample to determine the level of amyloid precursor protein (APP)-specific CD8+ T cells, using MHC multimers labeled with detection agents

Methodology Applied

Scientific EffectMHC multimer binding:

Implementation Method 2

administering therapeutic agents such as APP peptide-specific MHC multimers conjugated to cytotoxic agents to treat subjects with elevated APP-specific CD8+ T cell levels

Methodology Applied

Scientific EffectCytotoxicity:

Data Source

PatentUS20230333091A1Novel blood cell biomarker for late onset alzheimer's disease

Publication Date: 2023.10.19 CEDARS SINAI MEDICAL CENT

AI summary

Described herein are compositions and methods for diagnosing late-onset Alzheimer's disease (LOAD), Alzheimer's disease, or a predisposition to Alzheimer's disease and treating these disease conditions and assessing efficacy of therapeutic agents and immunomodulators. In aspects, late onset Alzheimer's disease (LOAD) is detected by decreased levels of amyloid precursor protein (APP) specific CD8+ T cells in blood and/or increased levels in brain tissue of a patient.