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Tangle of Tau proteins

Stabilizing protein Tau

BACE1

Complementactivation

Phagocytosis

Phagocytosis

Cytokine productioneg., TNFα secretion

Neurodegeneration

activation

TREM2

CR1CLU

Loss offunction in AD?

Loss offunction in AD?

Transcription

M I C R O G L I A

N E U R O N

Apoptoticcell bodiesHinders repair

Aβ build-up and plaque formationNeurotoxic

APPs

Aβ

A

B

B

Astrocyte

Microglia

ApoE4

Healthy microtubule

Alzheimer’s microtubule

Healthy microtubule

Alzheimer’s microtubuleAmyloidplaque

Tau tangles

A

Potential treatments

β-secretase inhibitors

Notch-sparing γ-secretase inhibitors or modulators

Aβ vaccines and monoclonal antibodies

Aβ aggregation inhibitors

Tau-lowering or anti-aggregation compounds

Regulators of abnormal

Aβ dimers and higher oligomers bind to neuronsand alter membrane protein function

ApoE4 proteindecreases clearanceof extracellular Aβ

Aβ monomers help regulatenormal synaptic transmission

MARK, GSK3,other kinase activities

Tau release extracellularlyand “pathogenic spread”?

APP, PS1, and PS2 mutationsincrease relative Aβ42 production

One APP mutation decreasesAβ production and prevents AD

PS-γAICD

APP processing

Aβ

Aβ

Aβ

X

TREM1TREM1

X

SnapShot: Pathobiology of Alzheimer’s DiseaseDennis J. SelkoeCenter for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA

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