Low-Frequency Repetitive Transcranial Magnetic Stimulation Ameliorates Cognitive Function and Synaptic Plasticity in APP23/PS45 Mouse Model of Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is a chronic neurodegenerative disease leading to dementia, which is characterized by progressive memory loss and other cognitive dysfunctions. Recent studies have attested that noninvasive repetitive transcranial magnetic stimulation (rTMS) may help improve cognitive function in patients with AD. However, the majority of these studies have focused on the effects of high-frequency rTMS on cognitive function, and little is known about low-frequency rTMS in AD treatment. Furthermore, the potential mechanisms of rTMS on the improvement of learning and memory also remain poorly understood. In the present study, we reported that severe deficits in spatial learning and memory were observed in APP23/PS45 double transgenic mice, a well known mouse model of AD. Furthermore, these behavioral changes were accompanied by the impairment of long-term potentiation (LTP) in the CA1 region of hippocampus, a brain region vital to spatial learning and memory. More importantly, 2-week low-frequency rTMS treatment markedly reversed the impairment of spatial learning and memory as well as hippocampal CA1 LTP. In addition, low-frequency rTMS dramatically reduced amyloid-β precursor protein (APP) and its C-terminal fragments (CTFs) including C99 and C89, as well as β-site APP-cleaving enzyme 1 (BACE1) in the hippocampus. These results indicate that low-frequency rTMS noninvasively and effectively ameliorates cognitive and synaptic functions in a mouse model of AD, and the potential mechanisms may be attributed to rTMS-induced reduction in Aβ neuropathology.

Transcranial Magnetic Stimulation in Alzheimer’s Disease: Are We Ready?

“…Nonetheless, substantial evidence indicates that neuronal activity promotes amyloid deposition, raising the possibility that the same highfrequency stimulation that leads to improved clinical symptoms might also accelerate underlying AD pathogenesis. Conversely, low-frequency rTMS reportedly decreases amyloid burden in the brains of AD transgenic mice (Huang et al, 2017), while preserving the reported cognitive benefit of high-frequency stimulation. Finally, perhaps the most hopeful target of TMS in AD-that intervening before symptom onset might correct contributing mechanisms or block seed events in the initiation of the disease process-remains largely untested.…”

TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease

“…Mice (4 months old) were deeply anesthetized with urethane (1.5 g/kg, i.p.) and transcardially perfused with artificial cerebral spinal fluid (ACSF) (in mM: NaCl 124, KCl 2.8, NaH 2 PO 4 .H 2 O 1.25, CaCl 2 2.0, MgSO 4 1.2, Na‐vitamin C 0.4, NaHCO 3 26, Na‐lactate 2.0, Na‐pyruvate 2.0 and D‐glucose 10.0, pH = 7.4) prior to decapitation as described previously (Du et al, ; Huang et al, ). Then, hippocampal slices were coronally sectioned (400 μm) with a vibratome (VT1200S, Leica Microsystems, Bannockburn, IL) with 95% O 2 and 5% CO 2 , and then were incubated in ACSF for 2 hr at 35°C.…”

MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

“…Mice (12 months old) were killed, and hippocampal slices (400-μm thick) were cut coronally with a vibratome (VT1200S, Leica, Wetzlar, Germany) at 95% O 2 and 5% CO 2 and then transferred into a submersion-type incubation chamber for a 2-h recovery at 35 °C. 52 Field excitatory postsynaptic potentials were recorded from hippocampal CA1 stratum radiatum by stimulation of the Schaffer collateral-commissural pathway. Theta burst stimulation was delivered to induce LTP after obtaining a stable baseline.…”