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Modulation of the endocytic, bioenergetic and transcriptomic pathways subserve the neuroprotective, anti-amyloidogenic action of cleavage-specific tau 12A12mAb in Alzheimer’s Disease mouse model

ABSTRACT: Beyond deficits in hippocampal-dependent episodic memory, Alzheimer’s Disease (AD) features sensory impairment in visual cognition consistent with extensive neuropathology in the retina. 12A12 is a monoclonal cleavage specific antibody (mAb) which in vivo selectively neutralizes the AD-relevant, harmful N-terminal 20-22kDa tau fragment(s) (i.e NH2htau) without altering the full-length normal protein. When systemically-injected into Tg2576 mouse model overexpressing a mutant form of Amyloid Precursor Protein (APP), APPK670/671L linked to early-onset familial AD, this conformation-specific tau mAb successfully neutralizes the NH2htau accumulating both in their brain and retina and, thus, markedly alleviates the phenotype-associated signs. By means of combined biochemical and metabolic and transcriptomic experimental approach, we report that 12A12mAb downregulates the steady state expression levels of APP and Beta-Secretase 1 (BACE-1) and, thus, limits the Amyloid beta (Aβ) production both in hippocampus and retina from this AD animal model. The endocytic (BIN1, RIN3) and bioenergetic (glycolisis and mitochondria) pathways controlling the cellular fate of APP processing towards the amyloidogenic route subserve the local, antibody-mediated anti-amyloidogenic action in vivo. Our results show for the first time that similar molecular and metabolic retino-cerebral pathways are modulated in coordinated fashion in response to 12A12mAb treatment to tackle the neurosensorial Aβ accumulation in AD neurodegeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE223593 | GEO | 2023/06/14

REPOSITORIES: GEO

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Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.

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Modulation of the endocytic, bioenergetic and transcriptomic pathways subserve the neuroprotective, anti-amyloidogenic action of cleavage-specific tau 12A12mAb in Alzheimer’s Disease mouse model

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