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Amyloid-beta Alzheimer targets - protein processing, lipid rafts, and amyloid-beta pores

Sage C Arbor¹, Mike LaFontaine¹, Medhane Cumbay¹

¹Marian University College of Osteopathic Medicine, 3200 Cold Spring Road, Indianapolis, Indiana, 46222.

The Yale Journal of Biology and Medicine

|August 10, 2016

Abstract:

Amyloid beta (Aβ), the hallmark of Alzheimer's Disease (AD), now appears to be deleterious in its low number aggregate form as opposed to the macroscopic Aβ fibers historically seen postmortem. While Alzheimer targets, such as the tau protein, amyloid precursor protein (APP) processing, and immune system activation continue to be investigated, the recent discovery that amyloid beta aggregates at lipid rafts and likely forms neurotoxic pores has led to a new paradigm regarding why past therapeutics may have failed and how to design the next round of compounds for clinical trials. An atomic resolution understanding of Aβ aggregates, which appear to exist in multiple conformations, is most desirable for future therapeutic development. The investigative difficulties, structures of these small Aβ aggregates, and current therapeutics are summarized in this review.

Insights

Small amyloid beta (Aβ) aggregates, not just large fibers, are toxic in Alzheimer's Disease (AD). Understanding these neurotoxic pores is key to developing new AD therapeutics.

Area of Science:

Neuroscience
Biochemistry
Pathology

Background:

Alzheimer's Disease (AD) is characterized by amyloid beta (Aβ) aggregates.
Historically, large Aβ fibers were considered the primary pathology.
Recent findings suggest smaller Aβ aggregates are also neurotoxic.

Purpose of the Study:

To review the emerging understanding of small amyloid beta (Aβ) aggregates.
To explore the role of Aβ aggregation at lipid rafts and pore formation.
To discuss implications for Alzheimer's Disease (AD) therapeutic development.

Main Methods:

Review of current literature on amyloid beta (Aβ) structure and function.
Analysis of recent discoveries regarding Aβ aggregation at lipid rafts.
Examination of existing and potential therapeutic strategies for Alzheimer's Disease (AD).

Main Results:

Small amyloid beta (Aβ) aggregates, not just macroscopic fibers, are now recognized as deleterious.
Amyloid beta (Aβ) aggregates at lipid rafts and may form neurotoxic pores.
Multiple conformations of Aβ aggregates exist, complicating structural studies.

Conclusions:

The formation of neurotoxic pores by small amyloid beta (Aβ) aggregates represents a new paradigm in Alzheimer's Disease (AD) pathology.
Understanding the atomic resolution structures of these Aβ aggregates is crucial for designing effective therapeutics.
This knowledge may explain the failure of past AD therapies and guide future clinical trials.

Read full analysis

Keywords:

APBA Alzheimer Amyloid ApoE Aß Mint amyloid precursor protein amyloid-beta cholesterol dementia ganglioside lipid raft perforin plaque pore presenilin secretase ß-barrel ß-secretase ß-strand γ-secretase

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