Unveiling AD Heterogeneity: Human vs. Mouse Seeds in Amyloid and Tau Pathology

Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder, is characterized by extracellular amyloid plaques (composed of amyloid-beta, Aβ) and intracellular neurofibrillary tangles (formed by hyperphosphorylated tau protein, p-tau). Research suggests that Aβ and tau proteins exhibit prion-like propagation, acting as “seeds” that induce misfolding of normal proteins, leading to aggregates that spread across the brain, causing neuronal damage and cognitive impairment. A key question arises: does the origin of these seeds (human or mouse) influence Alzheimer’s pathology? What role do microglia play in this process? While most studies focus on familial AD models, less is known about sporadic AD (LOAD). To address this, researchers utilized familial (3xTg-AD) and sporadic (hAβ-KI) mouse models to compare the effects of human and mouse AD seeds.

Experimental Design and Seed Preparation

Researchers collected protein aggregation-inducing “seeds” from human and mouse sources. Human AD seeds were derived from the prefrontal cortex of a 77-year-old female with Braak stage VI AD, a 79-year-old AD patient, and an age-matched cognitively normal female. Brain tissues were homogenized, sonicated, and centrifuged to obtain 10% PBS supernatant as “human AD seeds.” Mouse-derived “old-Tg seeds” were prepared from the brains of 25-month-old 3xTg-AD mice (carrying APP, MAPT, and PS1 mutations). Experiments utilized APP/PS1 and hAβ-KI mouse models, representing familial and sporadic AD, respectively.

Fig. 1. Experimental workflow and injection protocol

At 6–7 months of age, 3xTg-AD and hAβ-KI mice were anesthetized, and 2.5 μL of human AD or old-Tg seeds were unilaterally injected into the right hippocampus and neocortex using a stereotaxic apparatus (control groups received PBS). Another cohort of 3-month-old hAβ-KI and 2-month-old APP/PS1 mice received bilateral hippocampal injections of 10 μL human AD or non-demented homogenates. After injection, unilateral groups were incubated for 10 months (to 16–17 months of age), while bilateral hAβ-KI and APP/PS1 groups were incubated for 17 months (to 20 months) and 4 months (to 6 months), respectively. Brains were then fixed, and 40 μm coronal sections were prepared.

Results: Aβ and Tau Pathology

In 3xTg-AD mice, human AD seeds induced more severe Aβ pathology (marked by 6E10 and OC antibodies), accelerating diffuse and neuritic plaque formation.

Fig. 2. Hippocampal microscopy images showing ipsilateral and contralateral 6E10 immunostaining

In contrast, old-Tg seeds triggered more pronounced tau pathology, with elevated levels of phosphorylated tau (marked by AT8, MC1, and PHF1 antibodies).

Fig. 3. Hippocampal microscopy images with AT8 and PHF1 tau immunostaining

Old-Tg seeds reduced microglial clustering around plaques (marked by Iba1, CD45, CD68, P2RY12, and TREM2), exacerbating neuritic damage (marked by APP and Thio-S). Human AD seeds, however, maintained a microglial barrier, resulting in milder damage.

Fig. 4. Quantification of Iba1, P2RY12, and CD45-positive areas in ipsilateral and contralateral hippocampus

In hAβ-KI mice, no Aβ plaques formed, but human AD seeds increased PAS granules, indicating early degenerative changes. Overall, human AD seeds were more effective at inducing Aβ pathology, while old-Tg seeds were more potent in triggering tau pathology, reflecting differences in toxic strains.

Implications and Research Tools

These findings highlight the critical roles of seed origin, host model, and incubation time in AD pathology, providing insights into disease heterogeneity and informing therapeutic strategies for sporadic AD. abinScience specializes in developing and producing high-quality biological reagents, offering innovative tools for global researchers. abinScience provides a comprehensive product portfolio for autoimmune diseases, bacterial and viral infections, neuroscience, and immune target research. This includes antibodies, recombinant proteins, assay kits, and functional research tools, characterized by high sensitivity and specificity, supporting interdisciplinary and multidimensional research.

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