Molecular Differences and Similarities between Alzheimer's Disease and the 5XFAD Transgenic Mouse Model of Amyloidosis

Abstract

Transgenic (Tg) mouse models of Alzheimer’s disease (AD) have been extensively used to study the pathophysiology of this dementia and to test the efficacy of drugs to treat AD. The 5XFAD Tg mouse, which contains two presenilin-1 and three amyloid precursor protein (APP) mutations, was designed to rapidly recapitulate a portion of the pathologic alterations present in human AD. APP and its proteolytic peptides, as well as apolipoprotein E and endogenous mouse tau, were investigated in the 5XFAD mice at 3 months, 6 months, and 9 months. AD and nondemented subjects were used as a frame of reference. APP, amyloid-beta (Aβ) peptides, APP C-terminal fragments (CT99, CT83, AICD), β-site APP-cleaving enzyme, and APLP1 substantially increased with age in the brains of 5XFAD mice. Endogenous mouse tau did not show age-related differences. The rapid synthesis of Aβ and its impact on neuronal loss and neuroinflammation make the 5XFAD mice a desirable paradigm to model AD.

Can MRI T1 be used to detect early changes in 5xFAD Alzheimer’s mouse brain?

“…Therefore, these 5xFAD transgenic mice have been acknowledged as a useful model for better understanding the pathogenesis of human Alzheimer’s disease. In agreement with previous reports [22, 24], we found that first signs of amyloidosis and gliosis were detectable in the lower cortex and the corpus callosum of 2.5-month-old 5xFAD mice, although area fractions of GFAP staining and Iba-1 staining did not differ significantly from those of age-matched controls. However, significant increases in both astrocytosis and microgliosis, which occurred in parallel to significant increases in the Aβ area fraction, were found in the lower cortex, as well as in the corpus callosum of 5xFAD mice at the age of 5 months.…”

“…The 5xFAD transgenic mouse was developed by Oakley et al [22] to co-express five familial forms of Alzheimer’s disease [APP K670 N/M671L (Swedish) + I716 V (Florida) + V717I (London) and PS1 M146L + L286 V]. 5xFAD mice are characterised by the early development of Aβ plaques, neuroinflammation, neuronal loss, and memory impairment [22–24, 30, 31], all hallmarks of human Alzheimer’s disease. Therefore, these 5xFAD transgenic mice have been acknowledged as a useful model for better understanding the pathogenesis of human Alzheimer’s disease.…”

“…In previous work by the same authors, decreased T 1 values were found in patients with dementia with Lewy bodies compared with control subjects, highlighting the potential of T 1 measures in general to detect changes caused by neurodegeneration [21]. Using 5xFAD transgenic mice, a well-recognised AD mouse model [22–24], we have previously shown that at the age of 11 months, 5xFAD mice have reduced MRI T 1 relaxation times in the lower layers of the posterior parietal and primary somatosensory areas of the cortex and the corpus callosum compared with age-matched wild-type controls [25]. The cortex has a complex architecture that is made up of several layers, each defined by varying densities of myelin, neuronal cells, and receptors [26].…”

High‐Fat‐Diet Intake Enhances Cerebral Amyloid Angiopathy and Cognitive Impairment in a Mouse Model of Alzheimer's Disease, Independently of Metabolic Disorders

“…5XFAD mice overexpress human amyloid precursor protein (APP695) with Swedish (K670N, M671L), Florida (I716V), and London (V717I) familial AD mutations, also with mutant human presenilin‐1 (M146L, L286V) controlled by murine Thy‐1 promoter . 5XFAD mice generate Aβ 1–42 almost exclusively, rapidly accumulate amyloid plaque formation, and also recapitulate major pathologic and behavioral characteristics of AD . 5XFAD mice were backcrossed into the C57BL/6J background at least 10 generations to reduce genetic variation.…”

“…15 5XFAD mice generate Ab 1-42 almost exclusively, rapidly accumulate amyloid plaque formation, and also recapitulate major pathologic and behavioral characteristics of AD. [15][16][17] 5XFAD mice were backcrossed into the C57BL/6J background at least 10 generations to reduce genetic variation. The mice C57BL/6J (male) were purchased from SLC Japan (Shizuoka, Japan).…”