Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

Macyczko, Jesse R.; Wang, Na; Lü, Wenyan; Jeevaratnam, Suren; Shue, Francis; Martens, Yuka A.; Liu, Chia-Chen; Kanekiyo, Takahisa; Bu, Guojun; Li, Yonghe

doi:10.3233/jad-230218

Cited by 4 publications

(1 citation statement)

References 28 publications

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“…Notably, SFRP1 is significantly enriched in brain samples from different cohorts of AD patients, as compared to cognitively normal, age-matched individuals from preclinical stages of the disease 17,21–24 . A similar increase is also present in different AD mouse models, such as APP 695swe ;PS1 dE9 and 5xFAD, well before the appearance of amyloid plaques and neuroinflammatory signs 17,22,25 . Increased SFRP1 levels positively correlate with AD severity 17,22 and with the concentration of soluble Aβ peptides 17 .…”

Section: Introductionsupporting

confidence: 61%

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Pereyra,

Mateo,

Martin-Bermejo

et al. 2024

Preprint

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Decreased dendritic complexity and impaired synaptic function are strongly linked to cognitive decline in Alzheimer's disease (AD), and precede the emergence of other neuropathological traits that establish a harmful cycle exacerbating synaptic dysfunction. SFRP1, a glial-derived protein regulating cell-cell communication, is abnormally elevated in the brain of AD patients and related mouse models already at early disease stages. Neutralization of SFRP1 activity in mice reduces the occurrence of protein aggregates, neuroinflammation and prevents the loss of synaptic long-term potentiation (LTP). In this study, we generated transgenic mice that overexpress Sfrp1 in astrocytes to investigate whether LTP loss is due to an early influence of SFRP1 on synaptic function or results from other alterations driving disease progression. We report that SFRP1-overexpressing mice show reduced dendritic complexity and spine density in dentate gyrus granule cells during early adulthood, prior to a significant deficit in LTP response and late onset cognitive impairment. Ultrastructural analysis revealed the loss of small-sized synapses and presynaptic alterations in transgenic mice. Analysis of proteomic changes points to a general decrease in protein synthesis and modifications in the synaptic proteome, particularly of proteins related to synaptic vesicle cycle and synaptic organizers, like neurexin and neuroligin. We propose a model wherein SFRP1 directly impacts on synaptic function, by increasing the availability of synaptic organizing molecules at the synapse. These observations, combined with documented SFRP1 effects on APP processing and microglial activation, imply that SFRP1 contributes to multiple pathological effects in AD, emerging as a promising therapeutic target for this devastating disease.

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Section: Introductionsupporting

confidence: 61%

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Pereyra,

Mateo,

Martin-Bermejo

et al. 2024

Preprint

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Age- and Sex-Associated Wnt Signaling Dysregulation is Exacerbated from the Early Stages of Neuropathology in an Alzheimer’s Disease Model

Colín-Martínez,

Espino-de-la-Fuente,

Arias

2024

Neurochem Res

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Emerging studies suggest that Wnt signaling is dysregulated in the brains of AD patients, suggesting that this pathway may also contribute to disease progression. However, it remains to be determined whether alterations in the Wnt pathway are the cause or consequence of this disease and which elements of Wnt signaling mainly contribute to the appearance of AD histopathological markers early in disease compared to what occurs during normal aging. The present study aimed to describe the status of several canonical Wnt pathway components and the expression of the AD marker p-tau in the hippocampi of female and male 3xTg-AD mice during disease progression compared to those during normal aging. We analyzed the levels of the canonical Wnt components Wnt7a, Dkk-1, LRP6 and GSK3β as well as the levels of p-tau and BDNF at 3, 6, 9–12 and 18 months of age. We found a gradual increase in Dkk-1 levels during aging prior to Wnt7a and LRP5/6 depletion, which was strongly exacerbated in 3xTg-AD mice even at young ages and correlated with GSK3β activation and p-tau-S202/Thr205 expression. Dkk-1 upregulation, as well as the level of p-tau, was significantly greater in females than in males. Our results suggest that Dkk-1 upregulation is involved in the expression of several features of AD at early stages, which supports the possibility of positively modulating the canonical Wnt pathway as a therapeutic tool to delay this disease at early stages.

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Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling

Taha,

Birnbaum,

Matthews

et al. 2024

GeroScience

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Skeletal muscle regulates central nervous system (CNS) function and health, activating the muscle-to-brain axis through the secretion of skeletal muscle-originating factors (“myokines”) with neuroprotective properties. However, the precise mechanisms underlying these benefits in the context of Alzheimer’s disease (AD) remain poorly understood. To investigate muscle-to-brain axis signaling in response to amyloid β (Aβ)-induced toxicity, we generated 5xFAD transgenic female mice with enhanced skeletal muscle function (5xFAD;cTFEB;HSACre) at prodromal (4-months old) and late (8-months old) symptomatic stages. Skeletal muscle TFEB overexpression reduced Aβ plaque accumulation in the cortex and hippocampus at both ages and rescued behavioral neurocognitive deficits in 8-month-old 5xFAD mice. These changes were associated with transcriptional and protein remodeling of neurotrophic signaling and synaptic integrity, partially due to the CNS-targeting myokine prosaposin (PSAP). Our findings implicate the muscle-to-brain axis as a novel neuroprotective pathway against amyloid pathogenesis in AD.

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Upregulation of sFRP1 Is More Profound in Female than Male 5xFAD Mice and Positively Associated with Amyloid Pathology

Cited by 4 publications

References 28 publications

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

SFRP1 upregulation causes hippocampal synaptic dysfunction and memory impairment

Age- and Sex-Associated Wnt Signaling Dysregulation is Exacerbated from the Early Stages of Neuropathology in an Alzheimer’s Disease Model

Activation of the muscle-to-brain axis ameliorates neurocognitive deficits in an Alzheimer’s disease mouse model via enhancing neurotrophic and synaptic signaling

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