Tau is a component of the neurofibrillary tangles (NFTs) that are a hallmark pathology of Alzheimer's disease (AD). The staging of AD severity by the definitions described by Braak & Braak (1995) hinges on the extent of NFT spread in the brain.  Six stages of disease propagation can be distinguished with respect to the location of the tangle-bearing neurons and the severity of changes (transentorhinal stages I–II: clinically silent cases; limbic stages III–IV: incipient Alzheimer's disease; neocortical stages V–VI: fully developed Alzheimer's disease). Braak staging correlates with cognitive decline (Riley, Snowdon, Markesbery, 2002; see figure below).  Relevantly for this project, tau has been found to kill cholinergic neurons in wildtype mice when over expressed using viral methods and the decline of these cells is blamed in this study for reductions in spatial memory (Wu et al., 2021).

Tau factoids

Assume all quoted statements are direct quotes unless specified

• From this empirical paper

  • "Tau proteins normally play an important role in microtubule polymerization and axonal transport (Buee et al., 2000; Sergeant et al., 2008). Tau pathology results from the intracellular aggregation of hyperphosphorylated and abnormally phosphorylated Tau proteins into filaments and is encountered in many neurodegenerative disorders known as Tauopathies (Sergeant et al., 2008). In Alzheimer's disease (AD), Tau pathology leads to neurofibrillary degeneration (NFD), which appears first in the entorhinal cortex and hippocampal formation and then reaches isocortical areas (Braak and Braak, 1991; Delacourte et al., 1999). Several studies have outlined the relationship between the spreading of NFD and cognitive deficits (Duyckaerts et al., 1997; Grober et al., 1999) and suggest that Tau pathology plays a key role in the pathological cascade leading to AD symptoms."

• From this empirical paper

  • "At early stage of AD, tau preferentially accumulates in the excitatory neurons,13 resulting in the dysfunction of their excitability13, 14 and synaptic plasticity.15 Tau accumulation is also detected in GABAergic interneurons of hippocampal dentate gyrus (DG), where tau impairs hippocampal neurogenesis and increases neural stem cell-derived astrogliosis.16"

Nuggets from doing lit searches

"mouse model of alzheimer's disease tau"

• Beneficial effects of exercise in a transgenic mouse model of Alzheimer's disease-like Tau pathology

  • ► Long-term voluntary exercise prevents the development of memory impairment in a transgenic model of AD-like Tau pathology. 

    • Memory = exploration of novel arm of Y maze (5 min study, 2 min delay in homecage, 1 min test)

  • ► Long-term voluntary exercise reduces hippocampal Tau pathology and loss of ChAT expression in the medial septum. 

    • "we recently demonstrated a loss of ChAT immunoreactive neurons in the medial septum of 12-month-old THY-Tau22 mice (Belarbi et al., 2011)."

  • ► Beneficial effects are associated with an increased mRNA expression of NPC1 and NPC2.

• Specificity of anti-tau antibodies when analyzing mice models of Alzheimer's disease: problems and solutions

  • I didn't read this beyond the abstract yet, but it raises the point that antibody specificity is a concern in research on tau and warrants overt attention in experimental design.

  • Also relevant: G.S. Gibbons, R.A. Banks, B. Kim, L. Changolkar, D.M. Riddle, S.N. Leight, et al. Detection of Alzheimer disease (AD)-specific tau pathology in AD and nonAD tauopathies by immunohistochemistry with novel conformation-selective tau antibodies J. Neuropathol. Exp. Neurol., 77 (2018), pp. 216-228

"tau seeding mouse"

• Tau seeding mouse models with patient brain-derived aggregates

  • Great overall orientation to prior work with tau seeding in mice

• Emergence of early alterations in network oscillations and functional connectivity in a tau seeding mouse model of Alzheimer's disease pathology

  • Evidence of reduced theta power and a huge reduction in theta-gamma coupling in dCA1 in as little as 2 weeks after the seeding.

  • Used a unilateral seeding approach, using the contralateral hemisphere as a control.

  • Seeding was done in rCA1, tauopoathies remained unilateral in the hippocampus but were apparent bilaterally in the entorhinal cortex.

• Amyloid-β/Fyn–induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease

  • cross breeding tau-/- mice with an amyloid model (hAPP) results in a mouse that is less susceptable to amyloid-related toxicities

Key Themes

Tauopathies, generally

• NFTs have been identified in over 20 different neurodegenerative diseases collectively termed “tauopathies” (Murray, Kouri, Lin, Jack, Dickson, Vemuri, 2014; Spillantini & Goedert, 2013). 

• "[Tau] mutations, [...], are believed to cause disease via a toxic gain-of-function because tau is not required for neuronal survival, and mutations that affect alternative splicing of tau yet still produce wild type tau are also pathogenic [Andreadis, 2005]. Studies of these mutations show that they directly impact tau post-translational modifications, protein folding and aggregation, likely leading to toxic gain-of-function." 

Tauopathy progression in AD

• Both NFTs and neuropil threads begin in the transentorhinal region in the medial temporal lobar structures and progress to the neocortex and allocortex [Braak & Braak, 1991]. 

Tauopathy  and cognitive decline in AD

• "The number of NFT-positive cells correlates with disease stages, as measured by clinical parameters for cognitive decline and disease severity (Braak & Braak, 1991; Arriagada, Growdon, Hedley-Whyte, Hyman, 1992; Bierer, Hof, Purohit, Carlin, Schmeidler, Davis et al. 1995; Dickson, Crystal, Bevona, Honer, Vincent, Davies, 1995; Giannakopoulos, Herrmann, Bussiere, Bouras, Kovari, Perl et al., 2003). On the other hand, senile plaque density does not correlate with stages (Katzman, Terry, DeTeresa, Brown, Davies, Fuld, et al., 1988, Dickson, Crystal, Mattiace, Masur, Blau, Davies, et al., 1992, Delaère, Duychaerts, Masters, Beyreuther, Piette, Hauw 1990)."

  • NOTE: these are relevant but probably not fully inclusive. I found several weird things about the review I found this in.

Putative physiological bases for tau-related cognitive decline

• "Tau hyperphosphorylation and aggregation are associated with impaired long-term synaptic plasticity and short-term plasticity. In the hippocampus of numerous transgenic tau mouse models expressing human wild type tau (hTau and triple transgenic PLB1), tau mutants (including P301 L, K257 T/P301S, TauRDΔK280 expressing pro-aggregated 4R fragment K18) or a model of genetically-induced tau hyperphosphorylation by the PP2A inhibitor CIP2A, long-term potentiation (LTP) is reduced at an age correlated with an increase in tau phosphorylation and aggregation [[76], [77], [78], [79], [80], [81], [82], [83], [84], [85]]. Furthermore, LTP is reduced in mouse hippocampal slices by tau oligomers extracted from AD patient brains independent of soluble Aβ oligomers [86]. Reducing tau phosphorylation by inhibiting tau kinases restores tau-dependent LTP deficits and attenuates synaptic loss in tau transgenic mice [85,87]." - From this

• "Double acetyl-mimic at AD-related sites lysines 274 and 281 leads to tau mislocalization to somatodendritic compartments in primary cultures [139], and results in LTP deficits and impairment of memory formation in mice [106]." - Also from this

• RE progression of seeding "In AD, tau pathology may appear at a younger age than senile plaques do [145], though this timeline remains debatable. Braak suggests that tau pathology begins in the locus coeruleus and then spreads to other brainstem nuclei and to the entorhinal cortex." - Also from this

• RE differential seeding over varying tauopathies "Similar to the Braak stages, stereotypical temporospatial spreading of tau inclusions also occurs in other tauopathies such as argyrophilic grain disease. A key difference between these tauopathies is that the spread of tau progresses in different directions and to different brain regions [[146], [147], [148]]." - Also from this

• RE modulation of aggregation  - "Chaperone machinery provides a molecular mechanism involved in tau aggregation and degradation. A class of chaperones, such as DnaJA2, Hsp60, clusterin, Hsp104 and Hsc70, demonstrates activities in inhibiting tau aggregation and seeding-capacity of tau aggregates [168]. However, Hsp90, the most abundant chaperone in cells, shows a distinct function by promoting pathological tau stability and aggregation in the diseased state [169]. It remains unclear whether these chaperones are able to reverse already-formed tau fibrils [168,170]." - Also from this

• RE Propagation "recent studies have shown that tau can be secreted from neurons [[172], [173], [174], [175]].. . . The secretion of tau is dependent upon neuronal activity and varies between different tau isoforms [185]. " & "extracellular tau fibrils induce transmissible aggregation in recipient cells [[178], [179], [180]]. " & "Chemogenetic or optogenetic activation of neuronal activity increases tau release in primary neurons and is associated with brain hippocampus atrophy and tau pathology in P301 L mice [209]." - Also from this

  • PERSONAL NOTE: I wonder how this would play out in the cholinergic neurons? Would the activity increase propagation as cited above or, alternatively, would it protect the neurons which otherwise have a 'use it or lose it' phenotype and activity mediated lysosomal processing?

• RE Seeding "inoculation of pathological tau in tau transgenic mouse brains clearly demonstrates the transmission of tau pathology from one region to another [187]. Tau oligomers derived from AD patients that are injected into wild type mouse hippocampus cause memory impairments and the spread of phospho-tau to other regions of the brain including the cortex, corpus callosum and hypothalamus [188]. Confined expression of pro-aggregation P301 L tau in the entorhinal cortex using genetic approaches leads to anterograde spread to the dentate gyrus, CA1 and CA3 regions in two regulatable tau mouse models [189,190]." & "Tau derived from either AD, CBD or PSP patient brains that was injected into different brain regions spreads along neural networks independent of tau origin [208]." - Also from this

• RE modulation of seeding / propagation " Tau uptake and tau fibril seeding ability can be blocked chemically by inhibiting binding to HSPGs using heparin, chlorate or heparinase, or genetically by knocking down genes encoding enzymes involved in HSPG synthesis in neuroglioma cells, iPSC-derived neurons and mouse brain slice cultures [226,229,232]. "- Also from this

• RE Navigation related decline "[tau model] mice suffer from loss of excitatory neurons in the medial entorhinal cortex which are associated with spatial memory [191]."- Also from this

  • H. Fu, G.A. Rodriguez, M. Herman, S. Emrani, E. Nahmani, G. Barrett, et al. Tau pathology induces excitatory neuron loss, grid cell dysfunction, and spatial memory deficits reminiscent of early Alzheimer’s disease Neuron, 93 (2017), pp. 533-541

    • Differences visible @ 30 mohths but not 14 months

• RE connection to MCI cognitive decline "Elevated tau deposition in the neocortex was associated with mild cognitive impairment and worse scores on cognitive tests [287]. It remains to be investigated whether this timeline holds in sporadic AD cases."- Also from this

NFDs or tau is associated with reduced ChAT

• Cortical load of PHF-tau in Alzheimer's disease is correlated to cholinergic dysfunction 

  • (Arendt et al., 1999)

• Cholinergic and inflammatory phenotypes in transgenic tau mouse models of Alzheimer's disease and frontotemporal lobar degeneration 

  • (Cranston et al., 2020)

  • Describes state of cholinergic system in two tau models. Only one exhibits evidence of tau toxicity on the cholinergic system.

• Loss of medial septum cholinergic neurons in THY-Tau22 mouse model: what links with tau pathology? 

  • (Belarbi et al., 2011)

• Medial septum tau accumulation induces spatial memory deficit via disrupting medial septum–hippocampus cholinergic pathway

  • Wu et al. 2021

  • From abstract: "We found that hTau accumulation induced a time-dependent cholinergic neuron loss in MS and their projections to the hippocampus with a simultaneous spatial memory deficit. Intraperitoneal administration of donepezil, a cholinesterase inhibitor, for 1 month improved cognitive capacity and rescued cholinergic loss. Interestingly, donepezil induced a significant tau reduction and the effect of low-dose donepezil was more significant than high dose."

  • NOTE: used APP-related transgenic mice, hTau expression was virally triggered (pAAV-CAG-hTau-mCherry-3flag). Images show tau for WT, but I can't tell if they also received the virus.