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 (e.g., by increasing production of 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 two non-transgenic 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, non-transgenic models to study brain aging and AD, respectively.

Aging and brain free cholesterol concentration on amyloid‐β peptide accumulation in guinea pigs

“…Importantly, we have identified a role for brain free cholesterol on Aβ peptide accumulation in this model, with the involvement of Abca1 and Cyp46a1. As supported by the literature on the closeness of sequence homologies of Alzheimer's disease processing genes, cholesterol handling, and P-gp (Beck et al, 1997(Beck et al, , 2000(Beck et al, , 2003Fernandez & Volek, 2006;Pappas et al, 2014;Sharman et al, 2013;Wahl et al, 2022), we found that the changes in guinea pig with aging are similar to those in humans, other rodents or transgenic models that show cholesterol as a risk factor for Aβ processing.…”

“…The protein concentration was determined by the Lowry method (Lowry et al, 1951) prior to gel electrophoresis for immunoblotting. peptides are similar to those in man (Beck et al, 1997(Beck et al, , 2000Sharman et al, 2013;Wahl et al, 2022). The ELISA assays were performed according to an improved protocol for higher sensitivity since guinea pigs are non-transgenic and brain Aβ levels are several hundred-fold lower than those in counterpart transgenic models (Beck et al, 2003;Hsiao et al, 1996;Lu et al, 2016).…”

“…In vitro studies demonstrate that APP processing in guinea pig neuronal cells is identical to that in humans (Beck et al., 1997, 2000, 2003). The guinea pig displays nearly identical APP (97%) (Wahl et al., 2022), Abcb1 (87%) (Pappas et al., 2014), and Psen1/2 (presenilin 1 and 2, parts of the γ‐secretase enzyme complex) sequence homology to humans (Beck et al., 1997, 2000; Sharman et al., 2013), and aged guinea pigs develop diffuse Aβ deposits (Bates et al., 2013). One advantage is that the ELISA kits for hAβ 40 and hAβ 42 are readily utilized for the detection of guinea pig Aβ peptides in the frontal cortex and cerebrospinal fluid (CSF) due to the 100% identity of the Aβ 40 and Aβ 42 peptides to humans (Beach et al., 2001; Eketjäll et al., 2013; Hook et al., 2007; Ionov & Pushinskaya, 2010; Petanceska et al., 2000; Sharman et al., 2013; Steffen et al., 2016; Wahjoepramono et al., 2008).…”

Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline

“…Additionally, musculoskeletal function is not the only factor that dictates mobility. For example, we recently demonstrated that these guinea pigs exhibit hallmarks of human Alzheimer's disease that could explain impairments in integrative functional outcomes such as gait (Wahl et al., 2022). Thus, it is still important to assess additional and more specific components of musculoskeletal function, as mitochondrial function is a strong determinant in physical function such as gait speed and grip strength in humans (Gonzalez‐Freire et al., 2018).…”

“…The aim of our study was to determine whether long term supplementation of a phytochemical compound could ameliorate the progression of age-related OA and musculoskeletal decline documented in this model (Elliehausen et al, 2021;Minton et al, 2021;Musci et al, 2020). Further, our group has also documented that brains of these guinea pigs exhibit hallmarks of human brain ageing (Wahl et al, 2022). Future studies should focus on comparisons in these guinea pigs after the growth phase.…”