β-amyloid: The known unknowns

β-amyloid: The known unknowns

CHA

• Aß 약물의 잇다른 실패
  • 그동안 많은 병리학적/유전적/생화학적인 데이터로부터 Aß의 causative role을 설명해왔지만, 다른 설명이 있지 않을까?
• Aß의 주요 가정을 확인해보고, AD pathogenesis 조사를 실시한다

INTRODUCTION

• Causal role of Aß plaque in AD?
• Alzheimer가 1911년도에 원인고 동반하는 feature이라고 말함
  
• 알츠하이머가 묘사했고 pathogenic 아니라고 결론지음. 시퀀싱되면서 다운증후군과 함께 연구되었고 APP가 밝혀짐. 90년대에 계속 Aß와 APP가 연구됨. Aß42/40 비율이 제시되고 Presenilin이 Aß 생성에 관여한다고 밝혀짐. 그 외에 secretase 연구되고 PET ligand가 나타남
• 주로 familiar AD mutations과 monogenetic explanation for disease에 대해서 Aß hypothesis가 연구되어왔고 이에 대한 연구개발비가 엄청나게 투자되었음
• 하지만 현재 여전히 수많은 uncertainty, 즉 Known Unknowns
• to reinterpret the foundations for the Aß hypothesis

CONCLUSION

• 그동안 Aß 가설이 주요로 나왔지만 정말로 causative role을 하는가에 대한 것은 35년동안 불분명했다

sporadic AD에서 Aß가 causal factor인가?

1. 임상시험 실패

2. Aß plaque와 AD 결과 간의 multidimensional association 결여
   1.2.1. Disconnect with time

    - Aß PET 추적연구
    - ::플라크가 인지 저하와 신경퇴화와는 관련이 없다::
    - ::plaque는 단순히 신경퇴화의 위험을 높이는 과정의 biomarker 뿐이다::

   1.2.2. Disconnect with quantity

    - ::plaque와 질병 심각도와는 관련이 없다::
    - asymptomatic people with Aß burden

   1.2.3. Disconnect with anatomical location

    - Entorhinal, Hippocampus
    - temporal, occipital lobes
    - ::a temporal-spatial distribution pattern that does not match the temporal-spatial neurodegeneration pattern::
    - Aß가 질병의 바이오마커가 될 수 있다.
        - differential diagnosis of dementia
        - diagnosis of prodromal disease
            - CN with Aß <-  higher risk of future cognitive decline

3. Unknown 1: is Aβ a causal factor in sporadic AD?

   1. Every person with Alzheimer’s disease has extensive plaque deposition.
   2. Soluble, not plaque pathology is responsible for damage in AD.
   3. Aβ lowering drugs were administered too late in the disease to be effective.
4. 1. Failed Aβ clinical trials argue against a causal role for Aβ in AD

5. Unknown 2: does Aβ employ tau to damage neurons?

   1. FAD mutations cause tangle pathology
   2. Plaque pathology precedes NFT pathology

6. Unknown 3: do APP mutations cause disease by altering the generation of Aβ?

   1. Duplication of APP in Down syndrome or in rare familial cases causes Aβ •While every person with Down syndrome develops pathology with age, not everyone develops pathology.
   2. One rare mutation in APP (A673 T) that lowers Aβ production decreases the risk of AD.

7. Unknown 4: do presenilin mutations impact on FAD pathogenesis through Aβ?

   1. Mutations in presenilin 1/2 and APP - genes that are required for Aβ •There are no mutations that cause FAD in other genes required to make Aβ (nicastrin, PEN-2, production - cause familial Alzheimer’s disease
   2. It is not the abundance of Aβ but the increased ratio of longer Aβ species (42 & 43) to shorter species (38 & 40) that causes AD with presenilin mutations.

8. Unknown 5: does APOE ε4 increase risk through Aβ?

   1. ApoE (especially the ε4 isoform) has been shown to strongly inhibit the clearance of Aβ in mouse models by competing for the same receptors (LRP1).

9. Unknown 6: does Aβ have a function?

   1. Aβ is functionless so there is no harm in removing it