B lymphocytes ameliorate Alzheimer’s disease-like neuropathology via interleukin-35

The balance between regulatory and effector B cell subsets, rather than the presence or absence of B cells per se, is the critical determinant of outcome.

“This implies that the balance between regulatory and effector B cell subsets, rather than the presence or absence of B cells per se, is the critical determinant of outcome.”

Longitudinal analysis of B cells during AD progression in 5xFAD mice revealed a significant increase in CD19+ B lymphocytes in the frontal cortex and meninges at 3 months of age, compared to age-matched WT controls, while no differences were detected in the spleen.

“Longitudinal analysis of B cells during AD progression in 5xFAD mice revealed a significant increase in CD19 + B lymphocytes in the frontal cortex and meninges at 3 months of age, compared to age-matched wildtype (WT) controls, while no differences were detected in the spleen [107].”

Transient depletion of B cells in the 5xFAD model using either anti-CD20 or a mix of anti-CD20/B220 antibodies led to different pathological outcomes.

“transient depletion of B cells in the 5xFAD model of AD, using either anti-CD20 or a mix of anti-CD20/B220 antibodies led to different pathological outcomes [107,108].”

These findings collectively highlight a complex and stage-dependent dynamic of B cell involvement in experimental models of AD.

“These findings collectively highlight a complex and stage-dependent dynamic of B cell involvement in experimental models of AD.”

In another study using three different experimental models of AD pathology (3xTgAD, APP/PS1 and 5xFAD), B cells were found in the brain parenchyma of 8-11 months-old 5xFAD mice but their numbers were increased compared to age-matched WT controls.

“In another study using three different experi­ mental models of AD pathology (3xTgAD, APP/PS1 and 5xFAD), B cells were found in the brain parenchyma of 8 -11 months-old 5xFAD mice but in contrast to results from Feng et al., their numbers were increased compared to age-matched WT controls [107,108].”

The finding that IL-35-producing B cells are specifically detected in the frontal cortex of 5xFAD mice and that their ablation worsens Aβ pathology suggests that parenchymal B cells in this compartment are preferentially skewed towards a regulatory, neuroprotective phenotype.

“The finding that IL35-producing B cells are specifically detected in the frontal cortex of 5xFAD mice and that their ablation worsens A β pathology suggests that parenchymal B cells in this compartment are preferentially skewed to­ wards a regulatory, neuroprotective phenotype [107].”

Infiltrating B cells produced IL-35 in the cortex of 5xFAD mice.

“infiltrating B cells produced IL-35 in the cortex of 5xFAD mice”

The protective effects observed in 5xFAD mice appear to depend critically on the IL-35-producing B cell subset localized to the cortex.

“First, the protective effects observed in 5xFAD mice appear to depend critically on the IL-35producing B cell subset localized to the cortex”

In contrast, 2 months-old 5xFAD mice treated with anti-CD20 antibodies developed an aggravated disease.

“In contrast, 2 months-old 5xFAD mice treated with anti-CD20 antibodies developed an aggravated disease [107].”

IL-35 reduced Aβ pathology and neuroinflammation, as neutralizing IL-35 (via anti-Ebi3 antibodies) worsened Aβ deposition and cognitive deficits.

“an anti-inflammatory cytokine that reduced A β pathology and neuroinflammation as neutralizing IL-35 (via antiEbi3 antibodies) worsened A β deposition and cognitive deficits [107].”

5xFADμMT mice displayed increased Aβ plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits.

“5xFADμ MT mice displayed increased A β plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits [107].”

The dual role of B cells in AD is not a paradox but rather the product of heterogeneity in B cell subset identity, disease stage, and anatomical compartment.

“All together, these three scenarios suggest that the dual role of B cells in AD is not a paradox but rather the product of heterogeneity in B cell subset identity, disease stage, and anatomical compartment.”

Genetic and antibody-based B cell inactivation strategies in AD mouse models have yielded conflicting results.

“researchers have employed both genetic and antibody-based B cell inactivation strategies, though these approaches have yielded conflicting results.”

The apparently contradictory findings from B cell depletion studies in AD mouse models can be partially reconciled by considering three non-mutually exclusive mechanistic scenarios.

“These apparently contradictory findings from B cell depletion studies in AD mouse models whereby B cell deficiency worsens pathology in 5xFADμ MT mice yet improves it in 3xTgAD- and APP/PS1-JHT mice, and whereby transient depletion at different ages of the same model yields opposite outcomes can be partially reconciled by considering three non-mutually exclusive mechanistic sc”

These B cells are predominantly localized near amyloid lesions in both the brain parenchyma and meninges.

“Immunofluorescence studies further showed that these B cells are predominantly localized near amyloid lesions in both the brain paren­ chyma and meninges [107].”

As disease progresses, the proportion of CD19+ B cells in the frontal cortex and meninges either normalizes or decreases relative to WT controls by 5 and 8 months of age, respectively.

“as the disease progresses, the proportion of CD19 + B cells in the frontal cortex and meninges either normalizes or decreases relative to WT controls by 5 and 8 months of age, respectively [107].”

In 5xFAD mice with anti-CD20 depletion at 2 months, transient mature B cell depletion (early disease) aggravated Aβ pathology and cognitive deficits.

“Aggravated A β pathology and cognitive deficits [107]”

B cell depletion can either worsen or improve pathology depending on the model, strongly suggesting that B cell involvement is not merely reactive but functionally consequential.

“the finding that B cell depletion can either worsen or improve pathology depending on the model strongly suggests that B cell involvement is not merely reactive but functionally conse­ quential.”

In 5xFAD mice with IL-35 neutralisation (anti-Ebi3), Aβ deposition and cognitive deficits worsened.

“Worsened A β deposition and cognitive deficits [107]”

In 5xFAD longitudinal B cell analysis, CD19+ B cells in frontal cortex and meninges increased at 3 months and normalised/decreased by 5-8 months vs. WT.

“Increased at 3 months; normalised/decreased by 5 - 8 months vs. WT [107]”

In 5xFAD x μMT mice, absence of mature B cells increased Aβ plaque deposition, neuroinflammation, synaptic loss, and cognitive deficits.

“Increased A β plaque deposition, neuroinflammation, synaptic loss, cognitive deficits [107]”