Metformin attenuates plaque-associated tau pathology and reduces amyloid-β burden in APP/PS1 mice

Abstract

Background The neuropathological hallmarks of Alzheimer’s disease (AD) are amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aβ deposition precedes the aggregation of tau pathology and Aβ pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. Methods Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aβ pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. Results We observed tau aggregates in dystrophic neurites surrounding Aβ plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aβ plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aβ deposits and decreased the number of microglia around Aβ plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aβ plaques, promoted the phagocytosis of NP tau, and reduced Aβ load and NP tau pathology in APP/PS1 mice. Conclusion These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aβ and tau proteins by enhancing microglial autophagy capability. It reduced Aβ deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

Repurposing of Anti-Diabetic Agents as a New Opportunity to Alleviate Cognitive Impairment in Neurodegenerative and Neuropsychiatric Disorders

“…Metformin protected rats against from methamphetamine-induced neurodegeneration via the modulation of Akt/GSK3 or CREB/BDNF signaling pathway, and the amelioration of behavioral changes such as anxiety, depression and cognitive deficits( Keshavarzi et al, 2019 ). Metformin attenuated spatial memory deficits, neuron loss in the hippocampus, decreased Aβ plaque load and chronic inflammation in the hippocampus and cortex, and enhanced neurogenesis in the APP/PS1 mice, mouse model of AD( Ou et al, 2018 ; Chen et al, 2021 ). Metformin also restored spine density, surface AMPA subunit GluA1 trafficking, LTP expression and spatial memory in the APP/PS1 mouse by inhibiting cyclin-dependent kinase 5 hyper-activation and cyclin-dependent kinase 5-dependent tau hyperactivation( Wang et al, 2020 ).…”

Metformin a Potential Pharmacological Strategy in Late Onset Alzheimer’s Disease Treatment

“…Accumulation of Aβ increases the proinflammatory factors IL-1β and IL-6 levels in APP/PS1 mice [76]. It has been reported that metformin decreases the levels of IL-1β and IL-6 in APP/PS1 mice [76]. In addition, different studies have highlighted the anti-inflammatory and antioxidant function of metformin, with several pathways playing a key role in the activation of AMPK [147][148][149][150][151][152].…”

“…For the purpose of designing therapeutics or disease modifying agents for AD treatment, a wide variety of animal models have been developed to replicate the human environment of the disease [ 70 , 71 , 72 , 73 , 74 ]. In particular, the first aim of most AD animal models is to develop the neuropathological features that precede the cognitive dysfunction [ 75 , 76 , 77 ].…”

“…Transgenic mice models developed by over-expression of mutated human PS1, APP and tau, are the majority of these animal models. The triple-transgenic 3xTg-AD mice contains three mutated genes (human PS1M146V, APPSwe and tauP301L) and develops increasing age-dependent amyloid plaques and NFTs as well as memory deficits [ 76 , 77 , 78 ] ( Table 1 ).…”

“…On the other hand, many of the signature features of AD are reproduced by the injection of pharmacological or chemical agents into the brain or by the activation of lesions in specific brain regions [ 76 , 77 , 78 ]. For instance, the injection of Aβ peptide into the brain of rat or rhesus monkey has been used in several studies.…”