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In Alzheimer's disease (AD), β-amyloid (Aβ) plaques are tightly enveloped by microglia processes, but the significance of this phenomenon is unknown. Here we show that microglia constitute a barrier with profound impact on plaque composition and toxicity. Using high-resolution confocal and in vivo two-photon imaging in AD mouse models, we demonstrate that this barrier prevents outward plaque expansion and leads to compact plaque microregions with low Aβ42 affinity. Areas uncovered by microglia are less compact but have high Aβ42 affinity, leading to the formation of protofibrillar Aβ42 hotspots that are associated with more severe axonal dystrophy. In ageing, microglia coverage is reduced leading to enlarged protofibrillar Aβ42 hotspots and more severe neuritic dystrophy. CX3CR1 gene deletion or anti-Aβ immunotherapy causes expansion of microglia coverage and reduced neuritic dystrophy. Failure of the microglia barrier and the accumulation of neurotoxic protofibrillar Aβ hotspots may constitute novel therapeutic and clinical imaging targets for AD.

Haplodeficiency of the microglia gene TREM2 increases risk for late-onset Alzheimer's disease (AD) but the mechanisms remain uncertain. To investigate this, we used high-resolution confocal and super-resolution (STORM) microscopy in AD-like mice and human AD tissue. We found that microglia processes, rich in TREM2, tightly surround early amyloid fibrils and plaques promoting their compaction and insulation. In Trem2- or DAP12-haplodeficient mice and in humans with R47H TREM2 mutations, microglia had a markedly reduced ability to envelop amyloid deposits. This led to an increase in less compact plaques with longer and branched amyloid fibrils resulting in greater surface exposure to adjacent neurites. This was associated with more severe neuritic tau hyperphosphorylation and axonal dystrophy around amyloid deposits. Thus, TREM2 deficiency may disrupt the formation of a neuroprotective microglia barrier that regulates amyloid compaction and insulation. Pharmacological modulation of this barrier could be a novel therapeutic strategy for AD.

Aberrant neural hyperactivity has been observed in early stages of Alzheimer's disease (AD) and may be a driving force in the progression of amyloid pathology. Evidence for this includes the findings that neural activity may modulate amyloid (A) peptide secretion and experimental stimulation of neural activity can increase amyloid deposition. However, whether long-term attenuation of neural activity prevents the buildup of amyloid plaques and associated neural pathologies remains unknown. Using viral-mediated delivery of designer receptors exclusively activated by designer drugs (DREADDs), we show in two AD-like mouse models that chronic intermittent increases or reductions of activity have opposite effects on A deposition. Neural activity reduction markedly decreases A aggregation in regions containing axons or dendrites of DREADD-expressing neurons, suggesting the involvement of synaptic and nonsynaptic A release mechanisms. Importantly, activity attenuation is associated with a reduction in axonal dystrophy and synaptic loss around amyloid plaques. Thus, modulation of neural activity could constitute a potential therapeutic strategy for ameliorating amyloid-induced pathology in AD. [ABSTRACT FROM AUTHOR]

Dystrophic neurites are associated with fibrillar amyloid deposition in Alzheimer's disease (AD), but the frequency and types of changes in synaptic structures near amyloid deposits have not been well characterized. Using high-resolution confocal microscopy to image lipophilic dye-labeled dendrites and thioflavin-S-labeled amyloid plaques, we systematically analyzed the structural changes of dendrites associated with amyloid deposition in both a transgenic mouse model of AD (PSAPP) and in human postmortem brain. We found that in PSAPP mice, dendritic branches passing through or within 40 μm from amyloid deposits displayed various dendritic abnormalities such as loss of dendritic spines, shaft atrophy, bending, abrupt branch endings, varicosity formation, and sprouting. Similar structural alterations of dendrites were seen in postmortem human AD tissue, with spine loss as the most common abnormality in both PSAPP mice and human AD brains. These results demonstrate that fibrillar amyloid deposits and their surrounding microenvironment are toxic to dendrites and likely contribute to significant disruption of neuronal circuits in AD. [ABSTRACT FROM AUTHOR]

Amyloid plaques are a hallmark of Alzheimer disease, but their importance in its pathogenesis is controversial. By neuronal labeling and transcranial two-photon imaging, we show in a transgenic mouse model of Alzheimer disease that dendrites passing through or near fibrillar amyloid deposits undergo spine loss and shaft atrophy, and nearby axons develop large varicosities, together leading to neurite breakage and large- scale, permanent disruption of neuronal connections. Thus, fibrillar amyloid deposition is more detrimental to neuronal circuitry than previously thought, underscoring the importance of prevention and early clearance of plaques. [ABSTRACT FROM AUTHOR]