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ACKNOWLEDGMENTS
Funding:We thank the Dementia Research Institute [UKDRI
supported by the Medical Research Council (MRC), Alzheimer’s
Research UK, and Alzheimer’s Society], MRC Centre for
Neuropsychiatric Genetics and Genomics (MR/L010305/1),
Welsh Government, Joint Programming for Neurodegeneration
(JPND), VIB and KU Leuven (Methusalem grant), the European
Research Council (ERC) under the European Union’s Horizon 2020
research and innovation program (grant no. ERC-834682
CELLPHASE_AD), the“Fonds voor Wetenschappelijk Onderzoek,”
the“Geneeskundige Stichting Koningin Elisabeth,”Opening the
Future campaign of the Leuven Universitair Fonds, VLAIO ICON
Personalized Medicine grant (grant no. HBC.2019.2523“PRISMA”),
the Belgian Alzheimer Research Foundation, and the Alzheimer’s
Association USA. B.D.S. is a holder of the Bax-Vanluffelen Chair for
Alzheimer’s disease.Competing interests:B.D.S. is an ad hoc
consultant for various companies but has no direct financial
interest in the current manuscript.

10.1126/science.abb8575

REVIEW

Microglia modulate neurodegeneration in Alzheimer’s

and Parkinson’s diseases

Tim Bartels, Sebastiaan De Schepper, Soyon Hong*

Dementia is a rapidly rising global health crisis that silently disables families and ends lives and livelihoods

around the world. To date, however, no early biomarkers or effective therapies exist. It is now clear that brain

microglia are more than mere bystanders or amyloid phagocytes; they can act as governors of neuronal

function and homeostasis in the adult brain. Here, we highlight the fundamental role of microglia as tissue-

resident macrophages in neuronal health. Then, we suggest how chronic impairment in microglia-neuron cross-

talk may secure the permanence of the failure of synaptic and neuronal function and health in Alzheimer’s and

Parkinson’s diseases. Understanding how to assess and modulate microglia-neuron interactions critical for

brain health will be key to developing effective therapies for dementia.

I

t is becoming increasingly clear that amy-

loids are not necessarily the smoking gun

of neuronal dysfunction and cognitive de-

cline in neurodegenerative diseases. This

is displayed in centenarians who have

both apparently good cognitive health and

brains populated with amyloids ( 1 ). Epide-

miological data also point to the concept of

cognitive reserve, where certain individuals

appear more resilient to pathological changes

in their brains ( 2 ). Hence, a challenge in neu-

rodegeneration is to understand how certain

aging brains successfully maintain proper neu-

ronal function despite chronic amyloid build-

up, whereas others do not. Several genetic

studies have suggested that microglia, the

primary tissue-resident macrophages of the

brain, may be key in determining this success

( 3 , 4 ). Emerging data in developing, adult, and

diseased brains collectively suggest that mi-

croglia are critical to neuronal homeostasis

and health. These observations raise the ques-

tion of whether, and which, microglia-neuron

interactions may be impaired in Alzheimer’s

disease (AD) and Parkinson’s disease (PD) to

confer neurodegeneration. Insight into this

question will enable the development of meth-

ods to assess and modulate microglia-neuron

interactions in the aging brain and allow for a

desperately needed expansion of focus from clear-

ing amyloids alone to monitoring neuronal health

in biomarker and target engagement efforts.

Here, we propose several pathways by which

microglia may contribute to neuronal dysfunc-

tion in AD and PD. In AD, we focus specifically

on complement-mediated synaptic loss and

suggest that there are lipid-centric mecha-

nisms in microglia-neuron cross-talk at the

synapse. In PD, we discuss the potential roles

of tissue-resident macrophages in the brain and

gut in modulating amyloid spreading and tox-

icity, including lysosomal degradation pathways.

Microglia are central to neuronal function

and health

Genomic and proteomic tools indicate that

microglia, akin to other tissue-resident macro-

phages, are functionally diverse depending on

context—i.e., brain region, age, health, and

metabolic needs. [Region-specific microglial

heterogeneity and their interdependence on

neuronal microenvironment have recently been

reviewed ( 5 ).] Microglia constantly survey their

local milieu for signals of danger and injury,

including pathogens, disease stimuli, and ap-

optotic neurons. In addition to their immune

functions, microglia crucially support brain

development—for example, by sculpting neu-

ronal synapses in the developing brain. In the

adult brain, microglia perform multiple func-

tions, including monitoring changes in neuro-

nal activity, modulating learning and memory,

and acting as local phagocytes and damage

sensors in the brain parenchyma ( 6 – 12 ).

Many of these microglia-neuron interactions

are mediated by cell-cell signaling pathways,

including purinergic signaling, cytokines, neu-

rotransmitters, and neuropeptides ( 5 ). These

functions often require high energy expendi-

ture and mitochondrial metabolism, for which

microglia display metabolic flexibility in acute

hypoglycemic states ( 9 ). An intriguing ques-

tion is whether chronic mitochondrial dys-

function observed in AD and PD ( 13 , 14 ) impairs

microglia’s ability to be metabolically flexible

and thus properly monitor and govern neuro-

nal function and health. Notably, in models of

neuronal mitochondrial defect and neurode-

generation ( 15 ), glia accumulate lipid droplets,

which can modulate macrophage function. Al-

ternatively, lipid droplets accumulate with aging

in microglia ( 16 ), which raises the question

of whether improper lipid metabolism in aged

microglia underlies susceptibility to neurode-

generation in AD and PD. In support of this

hypothesis, various AD and PD risk factors, in-

cluding triggering receptor expressed on mye-

loid cells 2 (TREM2), apolipoprotein E (ApoE),

GBA1, and stearoyl-CoA-desaturase (SCD), have

66 2 OCTOBER 2020•VOL 370 ISSUE 6512 sciencemag.org SCIENCE

UK Dementia Research Institute, Institute of Neurology,

University College London, London WC1E 6BT, UK.

*Corresponding author. Email: [email protected]

NEURODEGENERATION