Electromagnetic treatment to old Alzheimer's mice reverses β-amyloid deposition, modifies cerebral blood flow, and provides selected cognitive benefit

Abstract

Few studies have investigated physiologic and cognitive effects of "long-term" electromagnetic field (EMF) exposure in humans or animals. Our recent studies have provided initial insight into the long-term impact of adulthood EMF exposure (GSM, pulsed/modulated, 918 MHz, 0.25-1.05 W/kg) by showing 6+ months of daily EMF treatment protects against or reverses cognitive impairment in Alzheimer's transgenic (Tg) mice, while even having cognitive benefit to normal mice. Mechanistically, EMF-induced cognitive benefits involve suppression of brain β-amyloid (Aβ) aggregation/deposition in Tg mice and brain mitochondrial enhancement in both Tg and normal mice. The present study extends this work by showing that daily EMF treatment given to very old (21-27 month) Tg mice over a 2-month period reverses their very advanced brain Aβ aggregation/deposition. These very old Tg mice and their normal littermates together showed an increase in general memory function in the Y-maze task, although not in more complex tasks. Measurement of both body and brain temperature at intervals during the 2-month EMF treatment, as well as in a separate group of Tg mice during a 12-day treatment period, revealed no appreciable increases in brain temperature (and no/slight increases in body temperature) during EMF "ON" periods. Thus, the neuropathologic/cognitive benefits of EMF treatment occur without brain hyperthermia. Finally, regional cerebral blood flow in cerebral cortex was determined to be reduced in both Tg and normal mice after 2 months of EMF treatment, most probably through cerebrovascular constriction induced by freed/disaggregated Aβ (Tg mice) and slight body hyperthermia during "ON" periods. These results demonstrate that long-term EMF treatment can provide general cognitive benefit to very old Alzheimer's Tg mice and normal mice, as well as reversal of advanced Aβ neuropathology in Tg mice without brain heating. Results further underscore the potential for EMF treatment against AD.

Conflict of interest statement

Competing Interests: Co-author Dr. Cesar Borlongan is a PLoS ONE Editorial Board member. Co-author Richard Gonzalez is founder and CEO of a small electronics company, SAI of Florida, Redington Beach, Florida 33708. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Cognitive performance of non-transgenic (NT) and APPsw transgenic (Tg) mice in the Y-maze task of spontaneous alternation (Fig. 1A) and the circular platform task of spatial/reference memory (Fig. 1B).

(Fig. 1A) Both NT and Tg mice given EMF treatment exhibited nearly significant increases in Y-maze percent alternation. For both genotypes combined, a significant increased in percent alternation was evident in EMF-treated mice. *p

Figure 2. Working memory in the radial arm water maze (RAWM) task pre-treatment, 1 month, and 1.5 months into EMF treatment for the naïve first trial (T1) and working memory trial (T5) of APPsw transgenic (Tg) and non-transgenic (NT) mice.

(Fig. 2A) Pre-treatment RAWM testing revealed Tg mice to be impaired vs. NT mice during working memory Trial 5 on the last block of testing. *p

Figure 3. Body and brain temperature measurements for non-transgenic (NT) and APPsw transgenic (Tg) mice recorded prior to the start of EMF treatment (control), and at 1 Day, 1 week, 3 weeks, and 6 weeks into EMF treatment.

Control NT and Tg mice (no EMF exposure) maintained stable body and brain temperatures throughout the 6 week recording period. By contrast, both NT and Tg mice being treated with EMF experienced small, but significant increases in body temperature during ON periods by 1 week into treatment and time points thereafter. Although brain temperature of EMF-treated Tg mice remained stable during ON periods through the 6 week recording period, EMF-treated NT exhibited small (but significant) increases in brain temperature during ON periods at 3 and 6 weeks into EMF treatment. *p#p<0.02 vs. NT control on that day.

Figure 4. Body and brain temperature measurements for APPsw+PS1 transgenic (Tg) mice recorded prior to the start of EMF treatment (control), as well as at 5 days and 12 days into EMF treatment.

For both control and treatment time points, there were no differences between EMF-treated and control Tg mice for either body or brain temperatures. No significant differences in OFF vs. ON temperatures (via paired t-test) were evident in EMF-treated Tg mice.

Figure 5. Regional cerebral blood flow (rCBF) in cerebral cortex of NT and Tg mice in Studies I and II obtained by Laser Doppler measurements at the end of their 2 month and 12-day EMF treatment periods, respectively.

(Fig. 5A) At 2 months into EMF treatment for Study I, APPsw transgenic (Tg) mice exhibited a significant 13% decrease in rCBF during ON vs. OFF periods. During ON periods, an even greater reduction in rCBF for EMF-treated Tg mice was evident when compared to Tg controls. *p★p<0.05 vs. No EMF; ★★p<0.0001 vs. No EMF. (Fig. 5C) At 12 days into EMF treatment for Study II's APPsw+PS1 (Tg) mice, a near-significant rCBF reduction of 19% was present in EMF-treated Tg mice during ON vs. OFF periods. †p = 0.10 for ON vs. OFF (paired t-test); #p<0.05 vs. Tg control during OFF period.

Figure 6. Brain Aβ deposition in APPsw transgenic (Tg) mice at 2 months after EMF treatment (Study I).

(Fig. 6A) Photomicrographs showing the visually evident decrease in Aβ deposition in both hippocampus (H) and entorhinal cortex (EC) of EMF-treated mice compared to control/sham mice. Micrometer bar = 50 µm. (Fig. 6B) Quantification of percent Aβ burdens from EMF-treated and control/sham Tg mice. Highly significant reductions in Aβ deposition/aggregation were present in both hippocampus (↓30%) and entorhinal cortex (↓24%) of EMF-treated mice. *p

Figure 7. Summary diagram depicting both confirmed and proposed mechanisms of long-term EMF action in normal mice and Alzheimer's transgenic (Tg) mice.

Long-term EMF actions that we have confirmed include prevention/reversal of brain Aβ aggregation, brain mitochondrial enhancement, and reduced cortical cerebral blood flow (CBF). These long-term EMF actions occur through slight/no increase in brain temperature and without increasing brain oxidative stress/damage.