Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice

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Combined targeting of pathways regulating synaptic formation and autophagy attenuates Alzheimer’s disease pathology in mice

Bjorkli, Christiana (author): Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway

Hemler, Mary (author): Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway

Julian, Joshua B. (author): Princeton Neuroscience Institute, Princeton University, NJ, Princeton, United States

Sandvig, Axel (author): Umeå universitet,Institutionen för samhällsmedicin och rehabilitering,Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway; Department of Clinical Neurosciences, Division of Neuro Head and Neck, Umeå University Hospital, Umeå, Sweden

Sandvig, Ioanna (author): Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St. Olav’s Hospital, Trondheim, Norway

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Department of Neuromedicine and Movement Science, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology, Trondheim, Norway; Department of Neurology, St Olav’s Hospital, Trondheim, Norway Princeton Neuroscience Institute, Princeton University, NJ, Princeton, United States (creator_code:org_t)

2022-08-16
2022
English.
In: Frontiers in Pharmacology. - : Frontiers Media S.A.. - 1663-9812. ; 13

Related links:: https://doi.org/10.3...; show more...; https://umu.diva-por... (primary) (Raw object); https://urn.kb.se/re...; https://doi.org/10.3...; show less...

Journal article (peer-reviewed)

Abstract Subject headings

All drug trials completed to date have fallen short of meeting the clinical endpoint of significantly slowing cognitive decline in Alzheimer’s disease (AD) patients. In this study, we repurposed two FDA-approved drugs, Fasudil and Lonafarnib, targeting synaptic formation (i.e., Wnt signaling) and cellular clearance (i.e., autophagic) pathways respectively, to test their therapeutic potential for attenuating AD-related pathology. We characterized our 3xTg AD mouse colony to select timepoints for separate and combinatorial treatment of both drugs while collecting cerebrospinal fluid (CSF) using an optimized microdialysis method. We found that treatment with Fasudil reduced Aβ at early and later stages of AD, whereas administration of Lonafarnib had no effect on Aβ, but did reduce tau, at early stages of the disease. Induction of autophagy led to increased size of amyloid plaques when administered at late phases of the disease. We show that combinatorial treatment with both drugs was effective at reducing intraneuronal Aβ and led to improved cognitive performance in mice. These findings lend support to regulating Wnt and autophagic pathways in order to attenuate AD-related pathology.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Farmakologi och toxikologi (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Pharmacology and Toxicology (hsv//eng)
MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)

Keyword

amyloid plaques
microdialysis
mTor pathway
neurofibrillary tangles
repurposed drugs
Wnt signalling

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MEDICAL AND HEALTH SCIENCES: MEDICAL AND HEAL ...; and Basic Medicine; and Pharmacology and ...

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