Microglia are involved in Alzheimer's disease in three key ways: 1) Active microglia release inflammatory molecules that are neurotoxic. 2) Microglia may not effectively clear amyloid plaques, accelerating AD pathology. 3) The developmental synaptic pruning pathway mediated by microglia is inappropriately activated in AD, leading to excessive synapse loss.

1. How microglia are involved in Alzheimer’s disease
Sensho Nobe
8/23/2021 Paper survery

2. 京都大学 理学部
→ 東京大学 理学系研究科 生物科学専攻 修士
→ 同 博士1年
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野辺 宣翔（のべ せんしょう）
修士研究のキーワード
• マウス
• オプトジェネティクス
• 幼若期-社会的隔離ストレス
• 内側前頭前野 (mPFC)
• 側坐核 (Nucleus accumbens)
• 手がかり(音)恐怖条件づけ
• Deep Lab Cut
• 神経回路の雌雄差

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What does it look like in the brain?

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N.Kasthuri, …, J.W.Lichtman, Cell (2015)
What does it look like in the brain?
7µm

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Neuron and Glia cells
Allen & Barres, Nature (2009)
Brain cells
Neuron, Microglia, etc.
20%
Astrocyte
40%
Oligodendrocyte
40%
According to “Principles of Neural Science
(5th Edition)” by E. Kandel…
• Microglial cells account for up to 16%
of total brain cells. (Gotz, Bodea & Goedert, Nature Reviews (2018))

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Neuron and Glia cells
Allen & Barres, Nature (2009)
Oligodendrocyte
• Wraps “myelin” around axons
• Myelin upregulates action potential propagation speed
Astrocyte
• Controls extracellular molecular density (ions,
neurotransmitters, etc)
• Provide neurons with nutrient and other molecules
from blood vessel through BBB
• Mechanical support
Microglia
• Will be explained!

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• Alzheimer’s disease (AD) in brief
• Microglia in brief
• Microglia and Alzheimer’s disease
• (My personal interests of glia cells: oligodendrocytes, adaptive myelination)
Contents

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The pathological evolution of Alzheimer’s disease
Masters et al., Nature Reviews (2015)
Pathology traits: amyloid level, Braak NFT stage, CREAD score, etc…
• Degeneration with loss of neurons and synapses

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Pathways leading to plaques and tangles
Masters et al., Nature Reviews (2015)

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The pathological evolution of Alzheimer’s disease
Medical Imaging & Technology Alliance “Amyloid PET imaging basics”
PET amyloid imaging
Rowe & Villemagne, The Journal of Nuclear Medicine (2011)

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Pathways leading to plaques and tangles
Masters et al., Nature Reviews (2015)

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• Alzheimer’s disease (AD) in brief
• Microglia in brief
• Microglia and Alzheimer’s disease
• (My personal interests of glia cells: oligodendrocytes, adaptive myelination)
Contents

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Neuron and Glia cells
Allen & Barres, Nature (2009)
Brain cells
Neuron, Microglia, etc.
20%
Astrocyte
40%
Oligodendrocyte
40%
According to “Principles of Neural Science
(5th Edition)” by E. Kandel…

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Microglia: macrophages in the brain
Ransohff & Cardona, Nature (2010)

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Microglia originate from yolk sac
Prinz, Erny & Hagemeyer, Nature Immunology (2017)

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Different origins of macrophages
Prinz & Priller, Nature Reviews (2014)

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• Alzheimer’s disease (AD) in brief
• Microglia in brief
• Microglia and Alzheimer’s disease
• (My personal interests of glia cells: oligodendrocytes, adaptive myelination)
Contents

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Functions of microglia
• Respond to nearly any CNS perturbation
(→ microglia activation)
• Clear apoptotic neurons/glias & debris
• Eliminate / maintain synapses for proper
neural circuit wiring
「ミクログリアの機能」脳科学辞典

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An example of microglia activation: MTX

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Microglia in development and ageing

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Functions of microglia
「ミクログリアの機能」脳科学辞典
• Respond to nearly any CNS perturbation
(→ microglia activation)
• Clear apoptotic neurons/glias & debris
• Eliminate / maintain synapses for proper
neural circuit wiring

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Microglia cluster around amyloid-β plaques
Masters et al., Nature Reviews (2015)
Ziegler-Waldkirch & Mayer-Luehmann, Frontiers in Cellular Neuroscience (2018)

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Clearance of amyloid plaques by microglia?

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Microglia may not be involved in Aβ plaque uptake
Grathwohl et al., Nature Neuroscience (2009)
6 months old 6 mo + 3 weeks
TKラインをGCV treatmentすると
免疫細胞のみが生存不可能になる

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Microglia: macrophages in the brain
「ミクログリアの機能」脳科学辞典
• Respond to nearly any CNS perturbation
(→ microglia activation)
• Clear apoptotic neurons/glias & debris
• Eliminate / maintain synapses for proper
neural circuit wiring

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Dynamic microglial processes constantly explore the surrounding environment
https://www.youtube.com/watch?v=XPsGiTVNVnU

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Microglia interact with synapses
• Resting-state microglia constantly make brief (~5min)
contacts with synapses
• Those contacts are neuronal activity dependent
• After ischemia, the duration of contacts are prolonged,
frequently followed by synapse loss

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Microglia-synapse contacts are neuronal activity dependent
Spontaneous Ca2+ transients

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Excessive synapse elimination in Alzheimer’s disease
https://graylab.ucdavis.edu/research/

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Microglia are involved in developmental syanptic pruning

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Complement-mediated synapse elimination in development and neurodegeneration
Stephan, Barres & Stevens, Annu. Rev. Neurosci. (2012)

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Excessive synapse elimination in Alzheimer’s disease
https://graylab.ucdavis.edu/research/

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Excessive synapse elimination by microglia in the AD brain
• Hypothesis: normal developmental synaptic pruning pathway (C1q, C3) is activated in the
AD brain and mediates synapse loss
• synapse density quantification in CA1
• familial AD-mutant human APP “J20” transgegnic mice

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C1q upregulation and deposition onto synapses precede pre-plaque synapse loss in J20 mice
Hong et al., Science (2016)
Synaptophysin:
presynaptic marker
PSD95:
postsynaptic marker
3 months old
1 month old
DG

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Oligomeric Aβ increases C1q and microglial phagocytic activity
Hong et al., Science (2016)
C1q WT
C1q KO

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Microglia engulf synapses via CR3 upon oligomeric Aβ
Hong et al., Science (2016)

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Summary
Microglia are suggested to be involved in Alzheimer’s disease in three ways:
• Inflammatory molecules released from active microglia are neuro-toxic
• Impairment in amyloid uptake by microglia accelerate AD pathology (debated)
• Synapse pruning system in development is inappropriately activated and mediates
synapse loss in AD