Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain

Abstract

The hypothesis that amyloid-␤ (A␤) peptides are the primary cause of Alzheimer's disease (AD) remains the best supported theory of AD pathogenesis. Yet, many observations are inconsistent with the hypothesis. A␤ peptides are generated when amyloid precursor protein (APP) is cleaved by presenilins, a process that also produces APP intracellular domain (AICD). We previously generated AICDoverexpressing transgenic mice that showed abnormal activation of GSK-3␤, a pathological feature of AD. We now report that these mice exhibit additional AD-like characteristics, including hyperphosphorylation and aggregation of tau, neurodegeneration and working memory deficits that are prevented by treatment with lithium, a GSK-3␤ inhibitor. Consistent with its potential role in AD pathogenesis, we find AICD levels to be elevated in brains from AD patients. The in vivo findings that AICD can contribute to AD pathology independently of A␤ have important therapeutic implications and may explain some observations that are discordant with the amyloid hypothesis.amyloid precursor protein ͉ neurodegeneration ͉ tau hyperphosphorylation A lzheimer's disease (AD) is a neurodegenerative disorder that begins with deficits in short-term memory and culminates in total loss of cognition and executive functions. Neuropathologically, the disease is characterized by the presence of extracellular plaques enriched in amyloid-beta (A␤) peptides and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein (1, 2). The A␤ peptides are produced by the proteolytic processing of amyloid precursor protein (APP) (3, 4), which is cleaved by 'secretases' to produce multiple fragments. According to the amyloid hypothesis, A␤ peptides are the primary causative agents of AD, (5, 6), and A␤ peptides have remained the focus of the vast majority of studies in this research area.However, it is becoming clear that the A␤ plaques or increased A␤ load per se are unlikely to be the sole cause of AD, because a significant proportion of people without dementia have A␤ deposits and clearance of A␤ plaques by active immunization produced no clinical benefits (7). Also, the loss of synapses and the presence of phospho-tau in tangles seem to be better correlated with disease severity than A␤ load (8). Moreover, the neurological deficits can be dissociated from A␤ load in several mouse models of AD (9, 10) as well as human AD (7) and the clinical drug trials aimed at reducing A␤ load (flurbiprofen) or its aggregation (tramiprosate) have yielded disappointing results. Although many factors could have influenced the failed drug trials and could be responsible for the discordant results in animal studies, the combined weight of these findings suggests that factors independent of A␤ also contribute to AD pathogenesis (11,12). Recently, soluble aggregates of A␤ peptides have been proposed to be the toxic agent (13). However, the molecular nature of such soluble aggregates is uncertain and their existence and precise composition remains debated (14, 15).The p...

Tip off the HAT– Epigenetic control of learning and memory byDrosophilaTip60

“…45 We previously demonstrated that Tip60 HAT action is critical for nervous system development and cognitive processes such as synaptic plasticity, axonal outgrowth and transport via its transcriptional regulation of genes enriched for a variety of specific neuronal processes. 40 Consistent with a role for Tip60 in nervous system function, our laboratory 7,17,30,34,[40][41][42][43][44]46 and others 7,30,[47][48][49][50] have shown that the HAT Tip60 is implicated in Alzheimer's disease (AD) based on its role in epigenetic neuronal gene control via its formation of a transcriptionally active complex with the processed C-terminal amyloid precursor protein (APP) intracellular domain (AICD). 30,43,47,48,[51][52][53][54][55][56][57] Loss of Tip60 HAT activity and/or improper recruitment of this complex to specific gene promoters causes epigenetic misregulation of a variety of genes causatively associated with neurodegeneratation.…”

“…30,43,47,48,[51][52][53][54][55][56][57] Loss of Tip60 HAT activity and/or improper recruitment of this complex to specific gene promoters causes epigenetic misregulation of a variety of genes causatively associated with neurodegeneratation. 30,43,47,50,51 During the past several years, my laboratory has published a compendium of studies characterizing a functional interaction between Tip60 and the APP-C terminus (AICD) in mediating multiple cognitive neuronal processes using Tip60; APP transgenic Drosophila we generated as a robust model system. 7,17,30,34,[40][41][42][43] To develop this system, we utilized well characterized APP Drosophila lines that express equivalent and moderate levels of either GAL 4 responsive full length human APP (hAPP695) or APP lacking the AICD domain (APP-dCT) 43,58,59 and adapted them to harbor our GAL4 responsive Drosophila Tip60 wild-type (Tip60 WT ) or dominant negative HAT mutant (Tip60 E431Q ) transgenes.…”

Maladie d’Alzheimer, peptide β-amyloïde et synapses

“…Au-delà du rôle de l'APP comme précurseur de peptides intervenant dans la MA, APP a une action physiologique neurotrophique et synaptogénique, soit comme protéine transmembranaire, soit par les fragments de clivage (CTF, C-terminal fragment et APPs) (Figure 1) [9,10]. Ces fragments de clivage ont encore été très peu étudiés, même si le fragment CTF semble avoir lui-même un rôle pathologique [11]. Le lien étant établi entre niveaux de peptides -amyloïdes et déclin cognitif, la question se pose des mécanismes par lesquels les oligomè-res A solubles affectent la mémoire.…”

AD's tangled tail

“…1 The surprise is that the mice develop the disease phenotype independently of β-amyloid, the extracellular fragment of amyloid-β (A4) precursor protein that many believe to be the prime suspect in Alzheimer's disease.Instead, the disease in these mice appears to be caused by an intracellular fragment of amyloid-β (A4) precursor protein (APP) that goes on to trigger both abnormal hyperphosphorylated microtubule-associated protein-τ (MAPT; FTDP-17; tau) phosphorylation and neuronal death-two hallmarks of human AD that are not seen in the most widely used mouse models.The model thus raises fresh doubts about whether β-amyloid (Aβ) is really the cause of pathology and instead points to the intracellular portion of APP as the real culprit in AD.Aβ is a byproduct of proteolytic processing of APP that accumulates on the outside of cells in amyloid plaques. Aβ is toxic to neurons and is often detected in the serum and brains of AD patients.…”

“…1 The surprise is that the mice develop the disease phenotype independently of β-amyloid, the extracellular fragment of amyloid-β (A4) precursor protein that many believe to be the prime suspect in Alzheimer's disease.…”