Unfolded p53 in the pathogenesis of Alzheimer's disease: is HIPK2 the link?

Abstract

p53 transcriptional activity depends mainly on posttranslational modifications and protein/protein interaction. Another important mechanism that controls p53 function is its conformational stability since p53 is an intrinsically unstable protein. An altered conformational state of p53, independent from point mutations, has been reported in tissues from patients with Alzheimer's disease (AD), leading to an impaired and dysfunctional response to stressors. Recent evidence shows that one of the activators that induces p53 posttranslational modification and wild-type conformational stability is homeodomain interacting protein kinase 2 (HIPK2). Hence, conditions that induce HIPK2 deregulation would result in a dysfunctional response to stressors by affecting p53 activity. Discovering the mechanisms of HIPK2 activation/inhibition and the ways to manipulate HIPK2 activity are an interesting option to affect several biological pathways, including those underlying AD. Soluble beta-amyloid peptides have recently been involved in HIPK2 degradation, in turn regulating the p53 conformational state and vulnerability to a noxious stimulus, before triggering the amyloidogenic cascade. Here we discuss about these findings and the potential relevance of HIPK2 as a target for AD and highlight the existence of a novel amyloid-based mechanism in AD potentially leading to the survival of injured dysfunctional cells.

Amyloid accumulation is a late event in sporadic Alzheimer's disease-like pathology in nontransgenic rats

“…Our findings strongly support the idea that Aβ accumulation alone may not be sufficient to cause dementia in AD [2, 26]. Aβ is secreted to the extracellular milieu of the brain; this milieu is in contact with cerebrospinal fluid where Aβ is also detectable and performs important normal functions in the central nervous system, including neurogenesis, modulation of ion channel activity, kinase activation, synaptic plasticity, protection from oxidative damage, and enhancement of neuronal survival [27, 28, 29]. Impaired Aβ clearance, not increased synthesis, is believed to be the cause of the pathological accumulation of Aβ [5, 30].…”

Plasma microRNA biomarker detection for mild cognitive impairment using differential correlation analysis

“…TP53 has been explored originally as a tumor suppressor, but recently reported about other aspects to control diseases such as aging and metabolism [33]. There are accumulated studies that the change of TP53 protein, its modification and conformation were observed in AD patient brains [34–36] and blood [37]. Intriguingly, Le et al demonstrated that miR-125b bound to 3’ untranslated region of TP53 mRNA and worked as a negative regulator of TP53 [38], which means a possible presence of negative feedback loop.…”

Senescence-accelerated OXYS rats: A model of age-related cognitive decline with relevance to abnormalities in Alzheimer disease

“…52 In other words, a physiological role of Aβ in the central nervous system has been documented. 88 Aβ is involved in ion channel modulation, kinase activation, regulation of cholesterol transport, protection against metal-induced oxidative damage, synaptic plasticity, neuronal survival, and transcriptional regulation of AD-associated genes. The pathological accumulation of Aβ, the canonical dysfunction of AD, is associated with an imbalance between its production and clearance as a result of diseasecausing changes in the processing of AβPP in the brain.…”