As neuronal supporters and immune surveyors, astrocytes and microglia are no mere bystanders to the neuronal mayhem that unfolds in Alzheimer’s disease. At the AD/PD meeting, held March 5-9 in Lisbon, scientists presented new twists on the relative contributions of the two cell types to various aspects of AD, including plaque and tangle accumulation, synaptic deterioration, brain atrophy, and cognitive decline. The upshot? Reactive astrocytes spell trouble for neurons and their synapses, and this holds true even among people who have no Aβ plaques. Microglia, on the other hand, transform from neuroprotectors to slayers only once plaques inundate the brain. In mouse models, where researchers could deplete and restore the cells, microglia polarize into several transcriptional states over the course of amyloidosis. These evolving states are paralleled by functional transitions, in that the cells initially seed Aβ plaques, and then compact them later on.

Several presentations that attempted to disentangle the role of astrocytes versus microglia came from collaborators and scientists in the lab of Tharick Pascoal at the University of Pittsburgh. The researchers looked for connections between fluid and imaging biomarkers of Aβ and tau pathology, glial activity, and synaptic loss among several human AD cohorts.

Bruna Bellaver, an assistant professor in Pascoal’s lab, studies how astrocyte reactivity contributes to AD pathophysiology. Previously, she reported that among cognitively healthy people who have amyloid plaques, tangle pathology only showed up on PET scans among those whose astrocytes were fired up, as gauged by elevated plasma GFAP (Jun 2023 news). As she described in Lisbon, Bellaver has extended this line of work to decipher how astrocyte reactivity mediates correlations among plaques, plasma p-tau217, ApoE, and cognitive impairment across the AD spectrum.

Bellaver’s newest analysis relied on data from more than 2,000 participants in four cohorts in the U.S., Canada, South Korea, and Chile. About half were cognitively healthy, and half had been diagnosed with mild cognitive impairment or AD. First, Bellaver investigated how astrocyte reactivity influenced the relationship between amyloid status, as gauged by PET or plasma Aβ42/40 levels, and plasma p-tau217. She found that across the AD continuum, plasma p-tau217 increased as a function of plaque burden, but only if astrocytes were reactive, as gauged by elevated plasma GFAP. In those with calm astrocytes, plaques did not rouse plasma p-tau217. This mediating effect was strongest among people who were cognitively impaired. These glia also mediated ApoE effects, such that ApoE4 potentiated the plaque-driven plasma p-tau217 only in people with reactive astrocytes.

Finally, Bellaver reported that astrocyte reactivity determined the heft of the cognitive blow dealt by amyloid and tau pathologies. While MMSE scores were unaffected by amyloid or p-tau217 alone, they dropped if reactive astrocytes accompanied either marker (image below). People with all three—Aβ plaques, high p-tau217, and reactive astrocytes—fared worst.

Bellaver speculates that astrocytes change when they sense amyloid buildup in the brain. “They get reactive and progressively lose neuroprotective functions and/or gain novel neurotoxic properties, disrupting brain homeostasis,” she wrote to Alzforum. This reactivity might preclude their ability to contain tau pathology, she speculated.

In Pascoal’s lab, Francieli Rohden used biomarker data to explore a related question: How do astrocytes and microglia contribute to synaptic loss that worsens over the course of AD? Rohden examined relationships among CSF biomarkers measured in 105 participants in the TRIAD cohort, and 373 from ADNI. Volunteers in both cohorts were classified based on cognitive and amyloid status. Rohden used CSF GFAP to gauge astrocyte reactivity, soluble TREM2 as a proxy for microglial activation, and pre- and post-synaptic proteins GAP43 and neurogranin released into the CSF as markers of damaged synapses. At AD/PD, Rohden reported that astrocyte reactivity correlated with both markers of synaptic destruction, regardless of amyloid or cognitive status.

The story was different for microglial activation, which only associated with GAP43 and neurogranin among people who had amyloid. In these participants, sTREM2 rose in step with GAP43, regardless of cognitive status, and with neurogranin among those who were cognitively impaired. These associations hinted that microglial activation might spur deterioration of pre-synapses earlier in disease, eventually compromising post-synapses later.

What explains ties between glial activity and synaptic damage? Rohden found that levels of CSF p-tau181 could fully predict the association between astrocyte reactivity and synaptic markers, regardless of Aβ or cognitive status. CSF p-tau181 also linked microglial activation with synaptic markers, but only among those with amyloid. Given that CSF p-tau181 is strongly linked to amyloid, how might it connect astrocytes to synaptic damage among those without a substantial plaque burden? The scientists speculated that Aβ oligomers might rile astrocytes, which then instigate the phosphorylation of tau. When p-tau congregates in pre-synapses, it gloms onto synaptic vesicles and might erode synaptic integrity.

One interpretation of Rohden’s findings is that once plaques are established in the brain, microglial activation becomes a liability. Shifty microglia were the focus of several presentations in Lisbon. Guilherme Povala, also of the Pascoal lab, used data from the TRIAD cohort to assess how activated microglia—this time, measured by TSPO-PET—related to brain atrophy throughout the AD continuum. TSPO is an outer mitochondrial membrane protein that rises in activated microglia, and can be measured with the tracer [11C]PBR28. For several regions of interest across the brain, Povala looked for associations between TSPO-PET and brain atrophy, which was measured with serial MRI scans over two years in 80 normal and 54 cognitively impaired volunteers.

What did he discover? Among those with normal cognition, the relationship between microglial activation and brain atrophy depended on amyloid status. In those without plaques, TSPO-PET correlated with higher regional volume, suggesting microglial activation was protective. In people with plaques, the relationship flipped, such that regions with higher TSPO-PET had more atrophy.

Among those with impaired cognition, all of whom had Aβ plaques, Povala uncovered a similar relationship, this time relative to tangle pathology. In people whose tangles were limited to early Braak stage regions, microglial activation correlated with more brain volume. The opposite was true when tau tangles had spread into later Braak regions, beyond the temporal lobe. For those people, riled microglia associated with brain shrinkage. Finally, Povala reported that regardless of clinical disease stage, microglial activation in the presence of amyloid and tangles predicted future cognitive decline.