High-Level Neuronal Expression of Aβ_1–42in Wild-Type Human Amyloid Protein Precursor Transgenic Mice: Synaptotoxicity without Plaque Formation

Abstract

Amyloid plaques are a neuropathological hallmark of Alzheimer's disease (AD), but their relationship to neurodegeneration and dementia remains controversial. In contrast, there is a good correlation in AD between cognitive decline and loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in specific brain regions. We used expression-matched transgenic mouse lines to compare the effects of different human amyloid protein precursors (hAPP) and their products on plaque formation and SYN-IR presynaptic terminals. Four distinct minigenes were generated encoding wild-type hAPP or hAPP carrying mutations that alter the production of amyloidogenic A␤ peptides. The platelet-derived growth factor ␤ chain promoter was used to express these constructs in neurons. hAPP mutations associated with familial AD (FAD) increased cerebral A␤ 1-42 levels, whereas an experimental mutation of the ␤-secretase cleavage site (671 M3I ) eliminated production of human A␤.High levels of A␤ 1-42 resulted in age-dependent formation of amyloid plaques in FAD-mutant hAPP mice but not in expression-matched wild-type hAPP mice. Yet, significant decreases in the density of SYN-IR presynaptic terminals were found in both groups of mice. Across mice from different transgenic lines, the density of SYN-IR presynaptic terminals correlated inversely with A␤ levels but not with hAPP levels or plaque load. We conclude that A␤ is synaptotoxic even in the absence of plaques and that high levels of A␤ 1-42 are insufficient to induce plaque formation in mice expressing wild-type hAPP. Our results support the emerging view that plaque-independent A␤ toxicity plays an important role in the development of synaptic deficits in AD and related conditions.

Expression of A152T human tau causes age‐dependent neuronal dysfunction and loss in transgenic mice

“…To increase the survival of mice coexpressing hAPP/Aβ and hTau‐A152T, we crossed hTau‐A152T (L1) mice with mice from hAPP line J9 (hAPP‐J9), which express hAPP/Aβ at lower levels than hAPP‐J20 mice 50, 54, 55, 56. Among 282 offspring from crosses of hTau‐A152T (L1) and hAPP‐J9 mice, only eight were triply transgenic (Fig 11E).…”

Differential transgene expression patterns in Alzheimer mouse models revealed by novel human amyloid precursor protein‐specific antibodies

“…Hence, a triple transgenic model that overexpresses the aforementioned hAPP Swedish and AD‐specific mutants of presenilin and tau has been created (Oddo et al ., 2003). Other mouse models that express hAPP without AD‐specific mutations and do not develop Aβ plaques were created to differentiate between pathological effects of hAPP overexpression and Aβ aggregate formation (Mucke et al ., 2000). Although these AD mouse models are based on the amyloid cascade hypothesis and on similar AD‐related mutations, the phenotypic outcome is different.…”

“…Impaired spatial learning, working memory and contextual fear conditioning were observed at the same age (King & Arendash, 2002) which is well before extracellular plaques appear in the brain of these mice starting in limbic and cortical structures at the age of 10 months (Hsiao et al ., 1996; Kawarabayashi et al ., 2001). We were also able to detect APP transgene expression in I5 mice which do not develop plaques but still show synaptic deficits later in age (Mucke et al ., 2000). In addition, the widespread hAPP expression in Tg2576 mice compared to I5 and 3xTg mice is reflected by the intense labelling on Western blots (Fig.…”

“…These mice have been used to test therapeutic strategies that aim at reducing Aβ generation, for example by treatment with β‐secretase inhibitors and by active and passive immunization approaches (Solomon et al ., 1996; Schenk et al ., 1999; Eketjall et al ., 2013). Interestingly, transgenic mice overexpressing hAPP without AD‐related mutations, like I5, barely develop any Aβ deposits at high age (Mucke et al ., 2000). However, mice overexpressing mutant hAPP Swedish display Aβ deposits starting at around 10 months of age, for example Tg2576 (Hsiao et al ., 1996), while mice overexpressing mutant hAPP Swedish in combination with mutant γ ‐secretase components generate Aβ deposits even faster, for example 5xFAD (Oakley et al ., 2006).…”

APP mouse models for Alzheimer's disease preclinical studies

“…Frequently used models include PDAPP (Games et al , 1995), Tg2576 (Hsiao et al , 1996), APP23 (Sturchler‐Pierrat et al , 1997), J20 (Mucke et al , 2000), and TgCRND8 (Chishti et al , 2001). The APP constructs differ among the lines: They include APP695, APP770, and minigenes.…”