Genetic context controls early microglia-synaptic interactions in mouse models of Alzheimer’s disease

Common features of Alzheimer’s disease (AD) include amyloid pathology, microglia activation and synaptic dysfunction, however, the causal relationships amongst them remains unclear. Further, human data suggest susceptibility and resilience to AD neuropathology is controlled by genetic context, a factor underexplored in mouse models. To this end, we leveraged viral strategies to label an AD-vulnerable neuronal circuit in CA1 dendrites projecting to the frontal cortex in genetically diverse C57BL/6J (B6) and PWK/PhJ (PWK) APP/PS1 mouse strains and used PLX5622 to non-invasively deplete brain microglia. Reconstructions of labeled neurons revealed microglia-dependent changes in dendritic spine density and morphology in B6 wild-type (WT) and APP/PS1 yet a marked stability of spines across PWK mice. We further showed that synaptic changes depend on direct microglia-dendrite interactions in B6.APP/PS1 but not PWK.APP/PS1 mice. Collectively, these results demonstrate that microglia-dependent synaptic alterations in a specific AD-vulnerable projection pathway are differentially controlled by genetic context.

[1]  Martin Fuhrmann,et al.  Microglial motility is modulated by neuronal activity and correlates with dendritic spine plasticity in the hippocampus of awake mice , 2023, eLife.

[2]  Tuan Leng Tay,et al.  Microglia states and nomenclature: A field at its crossroads , 2022, Neuron.

[3]  Julie A. Harris,et al.  Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia , 2022, Molecular neurodegeneration.

[4]  Ravi S. Pandey,et al.  LOAD2: A late‐onset Alzheimer’s disease mouse model expressing APOEε4, Trem2*R47H, and humanized amyloid‐beta , 2021, Alzheimer's & Dementia.

[5]  Erik B. Bloss,et al.  Hippocampal and thalamic afferents form distinct synaptic microcircuits in the mouse infralimbic frontal cortex. , 2021, Cell reports.

[6]  Timothy J. Hohman,et al.  Protective genes and pathways in Alzheimer’s disease: moving towards precision interventions , 2021, Molecular Neurodegeneration.

[7]  Roberto Araya,et al.  A spike-timing-dependent plasticity rule for dendritic spines , 2020, Nature Communications.

[8]  Robert W. Williams,et al.  Identifying the molecular systems that influence cognitive resilience to Alzheimer's disease in genetically diverse mice , 2020, Learning & memory.

[9]  Chao Zhang,et al.  Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer’s disease model , 2019, Nature Communications.

[10]  Christoph Preuss,et al.  Enhancing face validity of mouse models of Alzheimer’s disease with natural genetic variation , 2019, PLoS genetics.

[11]  M. Huentelman,et al.  Harnessing Genetic Complexity to Enhance Translatability of Alzheimer’s Disease Mouse Models: A Path toward Precision Medicine , 2019, Neuron.

[12]  Evan Z. Macosko,et al.  Single‐Cell RNA Sequencing of Microglia throughout the Mouse Lifespan and in the Injured Brain Reveals Complex Cell‐State Changes , 2019, Immunity.

[13]  B. Stevens,et al.  Microglia and the Brain: Complementary Partners in Development and Disease. , 2018, Annual review of cell and developmental biology.

[14]  A. Najafi,et al.  Replacement of microglia in the aged brain reverses cognitive, synaptic, and neuronal deficits in mice , 2018, Aging cell.

[15]  for the Alzheimer’s Disease Neuroimaging Initiative,et al.  Sex differences in Alzheimer disease — the gateway to precision medicine , 2018, Nature Reviews Neurology.

[16]  Mark S. Cembrowski,et al.  Single excitatory axons form clustered synapses onto CA1 pyramidal cell dendrites , 2018, Nature Neuroscience.

[17]  Beth Stevens,et al.  Microglia emerge as central players in brain disease , 2017, Nature Medicine.

[18]  Benjamin A. Logsdon,et al.  Model organism development and evaluation for late‐onset Alzheimer's disease: MODEL‐AD , 2017, Alzheimer's & Dementia.

[19]  Sandro Romani,et al.  Inhibitory suppression of heterogeneously tuned excitation enhances spatial coding in CA1 place cells , 2017, Nature Neuroscience.

[20]  L. Looger,et al.  A Designer AAV Variant Permits Efficient Retrograde Access to Projection Neurons , 2016, Neuron.

[21]  Ben A. Barres,et al.  Complement and microglia mediate early synapse loss in Alzheimer mouse models , 2016, Science.

[22]  A. Najafi,et al.  Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. , 2016, Brain : a journal of neurology.

[23]  Mark S. Cembrowski,et al.  Structured Dendritic Inhibition Supports Branch-Selective Integration in CA1 Pyramidal Cells , 2016, Neuron.

[24]  D. Nicholson,et al.  Evidence for Alzheimer’s disease-linked synapse loss and compensation in mouse and human hippocampal CA1 pyramidal neurons , 2015, Brain Structure and Function.

[25]  Susumu Tonegawa,et al.  Conjunctive input processing drives feature selectivity in hippocampal CA1 neurons , 2015, Nature Neuroscience.

[26]  Susanne Schoch,et al.  Dendritic Structural Degeneration Is Functionally Linked to Cellular Hyperexcitability in a Mouse Model of Alzheimer’s Disease , 2014, Neuron.

[27]  Christina M. Weaver,et al.  Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model , 2014, The Journal of comparative neurology.

[28]  J. Morrison,et al.  The ageing cortical synapse: hallmarks and implications for cognitive decline , 2012, Nature Reviews Neuroscience.

[29]  B. Lamb,et al.  Genetic loci modulating amyloid-beta levels in a mouse model of Alzheimer's disease , 2008, Neurobiology of Aging.

[30]  Karel Svoboda,et al.  Locally dynamic synaptic learning rules in pyramidal neuron dendrites , 2007, Nature.

[31]  R. Petersen,et al.  Alzheimer's disease and mild cognitive impairment. , 2007, Neurologic clinics.

[32]  M. Ohno,et al.  Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation , 2006, The Journal of Neuroscience.

[33]  Nelson Spruston,et al.  Distance-Dependent Differences in Synapse Number and AMPA Receptor Expression in Hippocampal CA1 Pyramidal Neurons , 2006, Neuron.

[34]  D. Borchelt,et al.  APP processing and amyloid deposition in mice haplo-insufficient for presenilin 1 , 2004, Neurobiology of Aging.

[35]  H. Kasai,et al.  Structure–stability–function relationships of dendritic spines , 2003, Trends in Neurosciences.

[36]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[37]  Yasushi Miyashita,et al.  Dendritic spine geometry is critical for AMPA receptor expression in hippocampal CA1 pyramidal neurons , 2001, Nature Neuroscience.

[38]  T. Freund,et al.  Total number and distribution of inhibitory and excitatory synapses on hippocampal CA1 pyramidal cells , 2001, Neuroscience.

[39]  J. Morrison,et al.  Life and death of neurons in the aging brain. , 1997, Science.

[40]  D. Kleinfeld,et al.  In vivo dendritic calcium dynamics in neocortical pyramidal neurons , 1997, Nature.

[41]  S. Levay,et al.  Synaptic patterns in the visual cortex of the cat and monkey. Electron microscopy of Golgi Preparations , 1973, The Journal of comparative neurology.

[42]  A. Masurkar.  Towards a circuit-level understanding of hippocampal CA1 dysfunction in Alzheimer's disease across anatomical axes. , 2018, Journal of Alzheimer's disease & Parkinsonism.

[43]  H. Braak,et al.  Neuropathological stageing of Alzheimer-related changes , 2004, Acta Neuropathologica.

[44]  Vijaya L. Melnick,et al.  Alzheimer’s Dementia , 1985, Contemporary Issues in Biomedicine, Ethics, and Society.