Imipramine, in Part through Tumor Necrosis Factor α Inhibition, Prevents Cognitive Decline and β-Amyloid Accumulation in a Mouse Model of Alzheimer's Disease

Abstract

Alzheimer's disease (AD), the most common form of dementia in the older people, is a multifactoral pathology, characterized by cognitive deficits, increase in cerebral deposition of the ␤-amyloid (A␤) peptide, neurofibrillary tangles, and neurodegeneration. Studies currently support a central role of neuroinflammation, through production of proinflammatory cytokines including excess tumor necrosis factor ␣ (TNF-␣) in the pathogenesis of AD, especially in A␤-induced cognitive deficits. Imipramine, a tricyclic antidepressant, has potent anti-inflammatory and neuroprotective effects. This study investigates the effect of imipramine on alterations of long-term and short-term memories, TNF-␣ expression, and amyloid precursor protein (APP) processing induced by intracerebroventricular injection of A␤25-35 in mice. Mice were treated with imipramine (10 mg/kg i.p. once a day for 13 days) from the day after the A␤25-35 injection. Memory function was evaluated in the water-maze (days 10 -14) and Y-maze (day 9) tests. TNF-␣ levels and APP processing were examined in the frontal cortex and the hippocampus (day 14). Imipramine significantly prevented memory deficits caused by A␤25-35 in the water-maze and Y-maze tests, and inhibited the TNF-␣ increase in the frontal cortex. Moreover, imipramine decreased the elevated levels of A␤ both in frontal cortex and hippocampus with different modulations of APP and C-terminal fragments of APP. So, imipramine prevents memory impairment through its intrinsic property to inhibit TNF-␣ and A␤ accumulation and may represent a potential candidate for AD treatment.Alzheimer's disease (AD), the most common form of dementia in older people is associated with cognitive deficits. Indeed, brains of individuals who have AD manifest massive neuronal and synaptic loss in certain areas that result in memory impairment and disorientation associated mainly with late stages of the disease. However, in the early stages, the etiology of these cognitive dysfunctions is unclear. AD is a multifactoral pathology, characterized not only by an increase in cerebral deposition of the ␤-amyloid (A␤) peptide, the major constituent of senile plaques that can potentially cause cognitive impairments, but also by neuroinflammation, oxidative damage, and neurodegeneration in critical brain regions (hippocampus, frontal cortex) also involved in memory and cognition

Time-Course and Regional Analyses of the Physiopathological Changes Induced after Cerebral Injection of an Amyloid β Fragment in Rats

“…17 We observed increases in APP processing and amyloidogenic pathway (C99 levels) in the frontal cortex at all time points, in the amygdala after 3 weeks, and in the hippocampus mainly after 1 and 2 weeks. We therefore confirmed the A␤ [25][26][27][28][29][30][31][32][33][34][35] influence on seeding of endogenous A␤ 1-40/42 proteins in the rodent brain, particularly highlighting differences over time and among structures.…”

“…15 Deposits of A␤ [25][26][27][28][29][30][31][32][33][34][35] peptide after its injection have not yet been characterized by IHC, for lack of specific and selective antibodies. However, Klementiev et al 16 and Chavant et al 17 reported an accumulation of A␤ immunolabeling in the hippocampus and cerebral cortex, induced 4 and 2 weeks, respectively, after the A␤ [25][26][27][28][29][30][31][32][33][34][35] injection. In the present study, we followed over time the cerebral localization of A␤ [25][26][27][28][29][30][31][32][33][34][35] after injection into the lateral ventricle by using an A␤ [25][26][27][28][29][30][31][32][33][34][35] -HLF-tagged peptide.…”

“…Klementiev et al 16 recently documented some evidence that contradicts this latter reservation. Moreover, very recently, Chavant et al 17 reported that, at 2 weeks after injection, A␤ [25][26][27][28][29][30][31][32][33][34][35] significantly increased APP processing in the hippocampus of mice.…”

Blockade of Tau Hyperphosphorylation and Aβ1–42 Generation by the Aminotetrahydrofuran Derivative ANAVEX2-73, a Mixed Muscarinic and σ1 Receptor Agonist, in a Nontransgenic Mouse Model of Alzheimer’s Disease

“…The toxicity induced after such central injection of the Ab 25-35 fragment in oligomeric form in mice and rats was repeatedly shown to result in neuroinflammation and reactive gliosis, pro-apoptotic caspases activity, oxidative stress, reduction in the number of neurons measured in hippocampal pyramidal cell layers, loss of cholinergic neurons, and memory deficits (Maurice et al, 1996;Delobette et al, 1997;Stepanichev et al, 2003Stepanichev et al, , 2004Stepanichev et al, , 2006Meunier et al, 2006;Klementiev et al, 2007;Chavant et al, 2010;Villard et al, 2009Villard et al, , 2011Zussy et al, 2011). It is at present widely used to detect the neuroprotective potential of new drugs and natural derivatives (Ruan et al, 2010;Kim et al, 2011;Lu et al, 2012;Wang et al, 2012;Yang et al, 2012).…”

“…Interestingly, the Ab 25-35 injection resulted not only in an aggressive amyloid toxicity but also in accumulation of endogenous Ab species and Tau hyperphosphorylation, as observed in AD physiopathology. One week after Ab [25][26][27][28][29][30][31][32][33][34][35] injection, APP and Ab 1-42 levels were increased in the hippocampus and cortex, Ab-expressing cells could be visualized using immunohistochemistry and b-secretase cleavage products, such as the C-terminal fragment C99, could be detected (Klementiev et al, 2007;Chavant et al, 2010;Zussy et al, 2011). Moreover, an increase in Tau phosphorylation on physiological or AD-related pathological epitopes induced by Ab 25-35 injection in mice was reported in several studies (Dudas et al, 2002;Klementiev et al, 2007;Deng et al, 2010).…”