Nontransgenic Guinea Pig Strains Exhibit Hallmarks of Human Brain Aging and Alzheimer's Disease

Abstract

Older age is the primary risk factor for most chronic diseases, including Alzheimer's disease (AD). Current preclinical models to study brain aging and AD are mainly transgenic and harbor mutations intended to mirror brain pathologies associated with human brain aging/AD (eg, by increasing production of the amyloid precursor protein, amyloid beta [Aβ], and/or phosphorylated tau, all of which are key pathological mediators of AD). Although these models may provide insight on pathophysiological processes in AD, none completely recapitulate the disease and its strong age-dependence, and there has been limited success in translating preclinical results and treatments to humans. Here, we describe 2 nontransgenic guinea pig (GP) models, a standard PigmEnTed (PET) strain, and lesser-studied Dunkin-Hartley (DH) strain, that may naturally mimic key features of brain aging and AD in humans. We show that brain aging in PET GP is transcriptomically similar to human brain aging, whereas older DH brains are transcriptomically more similar to human AD. Both strains/models also exhibit increased neurofilament light chain (NFL, a marker of neuronal damage) with aging, and DH animals display greater S100 calcium-binding protein B (S100β), ionized calcium-binding adapter molecule 1 (Iba1), and Aβ and phosphorylated tau-which are all important markers of neuroinflammation-associated AD. Collectively, our results suggest that both the PET and DH GP may be useful, nontransgenic models to study brain aging and AD, respectively.

Keywords: Alzheimer’s disease; Brain aging; Inflammation; Transcriptomics.

Figure 1.

RNA-seq on brain tissue from PET and DH GP models. (A) MA (M, log ratio; A, mean average) plot showing age-related increases and decreases in genes/transcripts (dark data points FDR < 0.1) in PET GPs (n = 8 per group, 4m/4f). (B) Most significant decreased and increased biological processes (gene ontology terms) in older versus younger PETs. (C) MA plot showing increases and decreases in genes/transcripts (dark data points FDR < 0.1) in older DH versus older PET GPs. (D) Most significant decreased and increased biological processes (gene ontology terms) when comparing older DH to older PET animals. DH = Dunkin-Hartley; GP = guinea pig; PET = PigmEnTed; FDR = false discovery rate.

Figure 2.

PET and DH GPs exhibit transcriptome changes that overlap with human brain aging and AD. (A) Venn diagram showing the number of common biological processes shared among human brain aging, AD, older DH, and older PET GPs. (B) Venn diagrams showing specific numbers of increased/decreased biological processes (gene ontology terms) common to human brain aging and older PET GPs. (C) Venn diagrams showing specific numbers of increased/decreased biological processes (gene ontology terms) common to human brain human AD and older DH GPs. AD = Alzheimer’s disease; DH = Dunkin-Hartley; GP = guinea pig; PET = PigmEnTed.

Figure 3.

Confirmation that PET and DH GPs exhibit changes in the expression of proteins associated with brain aging and AD. (A) IκBα quantification. (B) TOB2 quantification. *p < .05, **p < .01, ***p < .001, ****p < .0001. (C) Representative images of immunoblots (n = 6 per group, 3m/3f). AD = Alzheimer’s disease; DH = Dunkin-Hartley; GP = guinea pig; PET = PigmEnTed; TOB2 = Transducer of ERBB2, 2.

Figure 4.

PET and DH GPs exhibit age-related increases in circulating NFL and pathological features of brain aging and AD in the hippocampus. (A) Plasma NFL measured by digital (Simoa) ELISA (n = 8/group, 4m/4f). (B and C) Immunohistochemistry images of hippocampi showing increases in Aβ _1–42 and p-tau (Thr 181) aggregates, as well as markers microgliosis (Iba1+ cells) and activated astrocytes (S100β+ cells) in older (15 months) versus younger (5 months) animals (scale bar = 20 µm). Insets to show staining and demyelination at 15 months of age. (D) Greater Aβ _1–42 and p-tau in hippocampus of older DH compared to the older PET GPs (top). Quantitative cell counts of Iba1+ and S100b+ indicating gliosis in hippocampus (bottom). *p < .05, **p < .01, ****p < .0001. n = 8/group (4m/4f). AD = Alzheimer’s disease; DH = Dunkin-Hartley; GP = guinea pig; NFL = neurofilament light chain; PET = PigmEnTed.

Figure 5.

PET and DH GP strains exhibit age-related changes in protein synthesis. (A) Fractional synthesis rate (%) of new proteins in mixed fraction of prefrontal cortex tissue from older (15 months) to younger (5 months) PET and DH GPs. (B) Fractional synthesis rate (%) of new mitochondrial proteins in prefrontal cortex tissue from older (15 months) to young (5 months) PET and DH GPs. **p < .01, n = 6/group (3m/3f). AD = Alzheimer’s disease; DH = Dunkin-Hartley; GP = guinea pig; PET = PigmEnTed.