Beneficial effects of early pro-neurogenic and neuronal network dysfunction suppression based treatments in Alzheimer’s disease transgenic mice.

Abstract

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder, and is the leading cause of dementia. Histopathologically, AD is characterized by two major lesions: extracellular deposits of amyloid as diffuse and neuritic plaques composed of amyloid beta (Aβ) peptide, and intraneuronal neurofibrillary tangles (NFTs) composed of abnormally hyperphosphorylated tau protein. Alongside Aβ plaques and NFTs, impairments in neurogenesis and synaptic plasticity, and profound neurodegeneration are also major features of AD. As yet, there is no effective treatment for AD, and currently the five FDA approved drugs, available for AD treatment, provide only mild symptomatic benefit for a limited period of time.

During the last two decades, several clinical trials targeting the AD pathology at moderate to advanced stages of the disease have failed to meet the primary endpoint. Thus, a paradigm shift has occurred, and increasingly early AD pathology is being targeted to develop successful treatment. On similar lines, this thesis evaluated the effects of early disease mechanisms-based treatments in AD transgenic mouse models. Studies described in this thesis employed two therapeutic strategies: (1) a pro-neurogenic modality (neurotrophic factor small-molecule mimetic) and, (2) reducing neuronal network dysfunction (in the form of epileptic activity), at early stages of AD pathology, and evaluated their effects at early, moderate, and advanced stages of the disease.

The Specific Aim 1 of this thesis evaluated the effects of early neural regeneration-based treatment with a ciliary neurotrophic factor (CNTF) small-molecule mimetic, Peptide 021 (P021; Ac-DGGLAG-NH2), in a transgenic mouse model of familial AD, i.e., 3xTg-AD mouse that harbors mutated human amyloid β precursor protein (APP), tau, and presenilin 1 genes. The chronic treatment with compound P021, started at early stages of AD pathology, ameliorated dentate gyrus neurogenesis deficit, synaptic and dendritic loss, and cognitive impairment at moderate-to-severe stages of the disease in 3xTg-AD mice. P021 treatment also robustly decreased the tau pathology and mildly attenuated the Aβ pathology both at moderate and severe stages of the disease. This disease-modifying effect of compound P021 was found to be mediated via increased brain derived neurotrophic factor (BDNF) expression-induced decrease in glycogen synthase kinase-3-β (GSK3β) activity. Thus, Specific Aim 1 of this thesis demonstrated the beneficial effect of early, chronic treatment with a pro-neurogenic modality at moderate-to-severe stages of the disease pathology in a transgenic mouse model of AD.

The Specific Aim 2 of this thesis analyzed the effects of early neural regeneration-based treatment with the compound P021, on AD in the context of Down syndrome (DS) in Ts65Dn mice. DS, caused by trisomy 21, is a well-established genetic cause of early-onset AD. The Ts65Dn mice carry a trisomy that is analogous to DS trisomy, including a triple copy of the APP gene. The prenatal to early postnatal treatment with compound P021 ameliorated developmental delay during the early postnatal period and AD-like cognitive impairment in adult life in Ts65Dn mice. P021 treatment also increased the expression of synaptic plasticity markers. Thus, Specific Aim 2 of this thesis showed the beneficial effect of treatment with a pro-neurogenic modality, administered only during the early stages, at moderate-to advanced stages of cognitive impairment in a trisomic mouse model of DS.

The Specific Aim 3 of this thesis probed neuronal network dysfunction, in the form of epileptic activities, as a biomarker for early AD pathology in 3xTg-AD mice. Furthermore, it evaluated the effect of targeting early AD pathology on neuronal network dysfunction in these mice. Increased audiogenic seizure susceptibility and hippocampal CA3 hypersynchronous network activity was found at ~ 3 weeks of age (prior to Aβ plaque deposition, neurofibrillary pathology, and cognitive impairment) in 3xTg-AD mice. Both audiogenic seizure susceptibility and hippocampal CA3 hypersynchronous network activity in 3xTg-AD mice were attenuated either by passive immunization with anti-human APP/Aβ antibody (6E10) or by metabotropic glutamate receptor 5 (mGluR5) blockade with the selective antagonist, 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP). Remarkably, hypersynchronous network activity positively correlated with intraneuronal human APP/Aβ expression in hippocampal CA3 region. Thus, Specific Aim 3 of this thesis identified neuronal network dysfunction, in the form of epileptic activities, as a potential biomarker of early disease pathology in a transgenic mouse model of AD. Furthermore, it showed the beneficial effect of targeting the early AD pathology to suppress neuronal network dysfunction.

Overall, this thesis revealed the beneficial effects of targeting early disease pathology in AD transgenic mice. By employing a pro-neurogenic modality and by evaluating the neuronal network dysfunction in experimental mouse models of AD and DS, this thesis identified potential drug targets and therapeutic strategies for early treatment of AD.