Amyloid-Driven Tau Accumulation on Mitochondria Potentially Leads to Cognitive Deterioration in Alzheimer’s Disease

Abstract

Despite the well-accepted role of the two main neuropathological markers (β-amyloid and tau) in the progression of Alzheimer’s disease, the interaction and specific contribution of each of them is not fully elucidated. To address this question, in the present study, an adeno-associated virus (AAV9) carrying the mutant P301L form of human tau, was injected into the dorsal hippocampi of APP/PS1 transgenic mice or wild type mice (WT). Three months after injections, memory tasks, biochemical and immunohistochemical analysis were performed. We found that the overexpression of hTauP301L accelerates memory deficits in APP/PS1 mice, but it did not affect memory function of WT mice. Likewise, biochemical assays showed that only in the case of APP/PS1-hTauP301L injected mice, an important accumulation of tau was observed in the insoluble urea fraction. Similarly, electron microscopy images revealed that numerous clusters of tau immunoparticles appear at the dendrites of APP/PS1 injected mice and not in WT animals, suggesting that the presence of amyloid is necessary to induce tau aggregation. Interestingly, these tau immunoparticles accumulate in dendritic mitochondria in the APP/PS1 mice, whereas most of mitochondria in WT injected mice remain free of tau immunoparticles. Taken together, it seems that amyloid induces tau aggregation and accumulation in the dendritic mitochondria and subsequently may alter synapse function, thus, contributing to accelerate cognitive decline in APP/PS1 mice.

Dysfunction of Mitochondria in Alzheimer’s Disease: ANT and VDAC Interact with Toxic Proteins and Aid to Determine the Fate of Brain Cells

“…In animals that develop the typical symptoms of AD, mitochondrial abnormalities are observed in the embryonic stage and in juvenile mice, long before Aβ accumulation [ 29 ]. It has also been documented that tau and Aβ act synergistically to accelerate mitochondrial dysfunction in animal models [ 30 , 31 , 32 ], highlighting as well that the effects of tau on mitochondrial activity occur through the addition of Aβ [ 11 , 33 ]. Therefore, in terms of molecular pathogenesis, the proteinopathy, that is, the abnormal accumulation of misfolded proteins, and the mitochondrial dysfunction are pivotal characteristics that occur and concur together in AD, reinforcing each other to guide the progression of the disease in the brain.…”

“…Using biochemical, molecular, and electron microscopy studies on post-mortem AD brains or transgenic mouse brains, several groups have investigated the connection between Aβ and mitochondria and between tau and mitochondria. Aβ is associated with mitochondria [ 13 , 38 , 39 ] and is transported to the MIM through the translocase of the machinery of the MOM (i.e., TOM) [ 40 ]; pathological forms of tau are also localized in the mitochondria [ 7 , 41 ], interfering with mitochondrial function in different brain areas through multiple mechanisms [ 30 ].…”

Therapeutic Potential of P110 Peptide: New Insights into Treatment of Alzheimer’s Disease

“…Mitochondrial dysfunction involves reactive oxygen species (ROS) generation, disruption in the electron transport chain, calcium dyshomeostasis, and apoptosis [16,17]. Mitochondrial dynamics play an essential role in regulating metabolism across the brain, the impairment of which leads to the pathogenesis of many neurodegenerative diseases, including AD [18,19]. Excessive mitochondrial fission and reduced fusion lead to mitochondrial fragmentation, which has been observed in animal models and patients with AD [20][21][22].…”

Hypoxic and Hypercapnic Responses in Transgenic Murine Model of Alzheimer’s Disease Overexpressing Human AβPP: The Effects of Pretreatment with Memantine and Rivastigmine

“…Its main features are cognitive and neuropsychiatric symptoms, leading to progressive impairment and disability [ 1 , 2 , 3 ]. Neurodegeneration, decreased synaptic density, and depletion of brain neurotransmitters are considered to be consequences of pathological processes determined by progressive deposition of amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles of hyperphosphorylated tau protein [ 4 , 5 , 6 , 7 ]. In addition to cognitive impairment, respiratory distress is common in AD patients.…”