Abstract
BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. The important influence of congenital genetic aberrations on the development of AD provides a novel opportunity to initiate prenatal to early postnatal pharmacological treatment to address the role of this critical period of brain development in the disease.MethodsWe investigated for the first time the effect of oral treatment during prenatal to early postnatal development with a neurotrophic compound, P021 (Ac-DGGLAG-NH2), on neurobehavior and AD-like pathology in 3xTg-AD, a transgenic mouse model of AD. The transgenic and control wild-type female mice were treated from prenatal day 8 to postnatal day 21 with a custom-made diet containing P021 or a vehicle diet, followed by a standard diet. AD-type cognitive function and pathological features were studied during adulthood and old age.ResultsThe P021 treatment rescued cognitive deficits at 4 months, reduced abnormal hyperphosphorylation and accumulation of tau at known major AD neurofibrillary pathology–associated sites, and decreased Aβ plaque load at 22 months in 3xTg-AD mice. Prenatal to early postnatal treatment with P021 also ameliorated certain markers of postsynaptic deficits, including PSD-95 levels and CREB activity, and decreased one measure of neuroinflammation, GFAP level in the brain at 4 and 22 months in 3xTg mice.ConclusionsThese findings suggest that neurotrophic impairment during early development can be one of the etiopathogenic factors of AD and that the neurotrophic peptide mimetic is a potential early prevention strategy for this disease.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals
We found that treatment with Peptidergic compound 021 (P021) from prenatal day 8 till Postnatal day (PND) prevented cognitive deficits at 4 months, reduced tau and amyloid pathologies at months, and decreased postsynaptic deficits and neuroinflammation in the brain at both 4 and 22 months in 3xTg-AD mice
Prenatal to early postnatal treatment with P021 prevents cognitive deficits at ~ 4 months in 3xTg-AD mice In our previous studies, we found that P021 treatment for different periods at young or old age can rescue the cognitive impairment in mice and rats, and both tau and Aβ pathologies in 3xTg-AD mice [20, 23]
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of middle-aged to old individuals. The pathophysiological process of AD is believed to begin many years before the emergence of clinical symptoms. Alzheimer’s disease (AD) is the most common cause of dementia in middle-aged and old individuals, which contributes significantly to health care burden, especially because of the lack of an effective therapy due to its multifactorial and heterogeneous nature and involvement of several different etiopathogenic mechanisms [1, 2]. An estimated 5.7 million Americans suffer from AD; this number includes an estimated 5.5 million people 65 years of age and older, and approximately 200,000 individuals younger than 65 years of age who have the early-onset form of the disease [3]. Tau and Aβ pathologies occur several years before the onset of clinical symptoms [13, 14]. The development of drugs for early prevention and treatment is considered necessary research goals
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
