Hippocampal tau pathology is related to neuroanatomical connections: an ageing population-based study

Abstract

Deposits of abnormally phosphorylated tau protein are found in numerous neurodegenerative disorders; the 'tauopathies', which include Alzheimer's and Pick's diseases, but tau pathology is also found in the ageing brain. Variation in tau pathology in brain ageing and its relationship to development of tauopathies and cognitive impairment remains unclear. We aimed to determine the extent and pattern of spread of tau pathology in the hippocampus, a susceptible region important in dementia and milder states of memory impairment, using hippocampal samples from the elderly population-based Medical Research Council Cognitive Function and Ageing Study neuropathology cohort. Tau deposition was assessed in hippocampal anatomical sub-regions using the AT8 antibody to phosphorylated tau and isoform-specific antibodies to 3 and 4-repeat tau (RD3 and RD4). Abeta pathology was also assessed. In this population sample, which includes the full ageing spectrum from individuals with no cognitive impairment to those with dementia satisfying clinico-pathology criteria for Alzheimer's disease, we have demonstrated a high prevalence at death of tau pathology. AT8, Abeta, RD3 and RD4 showed similar regional distribution and increased RD3 was noted in late-stage ghost tangles. Abeta was shown to be a poor explanatory variable for tau pathology. Tau deposition progressed in a hierarchical manner. Hippocampal input regions and projection zones (such as lateral entorhinal cortex, CA1/subiculum border and outer molecular layer of dentate) were initially affected, with anterograde progression though the hippocampal circuitry. Six hippocampal tau anatomical stages were defined, each linking projectionally to their adjacent stages, suggesting spread of tau malfunction through neuroanatomical pathways in hippocampal ageing. These stages were significantly associated with dementia, and may provide a clinically useful tool in the clinico-pathological assessment of dementia and mild cognitive impairment.

Stress Acts Cumulatively To Precipitate Alzheimer's Disease-Like Tau Pathology and Cognitive Deficits

“…Clinical reports of GC hypersecretion in AD patients and in cases of mild cognitive impairment, a condition with a high conversion rate to AD (Hartmann et al, 1997;Weiner et al, 1997;Elgh et al, 2006;Wilson et al, 2007), prompted us to examine how elevated GC secretion, induced by chronic unpredictable stress, influences the pattern of tau phosphorylation in the hippocampus and PFC, brain regions that are established targets of the deleterious morphological and behavioral actions of stress and GC (Sousa et al, 2000;Cerqueira et al, 2007;Schubert et al, 2008;Sotiropoulos et al, 2008a) and among the first to show signs of AD neuropathology (Lace et al, 2009).…”

“…Working model of how stress acts cumulatively to induce TAU pathology and cognitive impairment. Repeated exposures to adverse life events (stress), accompanied by increased levels of GCs,induceTAUpathologyinacumulativemanner.TAUhyperphosphorylationisprobablystimulated secondarily to stress/GC-induced misprocessing of APP to amyloidogenic peptides such as amyloid ␤ andC99 (Sotiropoulosetal.,2008a;Cataniaetal.,2009).HyperphosphorylatedTAUaccumulatesand aggregatesinneuronalperikarya,leadingtoneuronaldystrophyanddysfunction.Thefirstdetrimental signs of stress are seen in the hippocampal and parahippocampal regions, gradually spreading to the PFC and other cortical regions; similar spatiotemporal patterns are observed in patients with Alzheimer's disease (Lace et al, 2009). Rat brain images were adapted from Swanson (1999).…”

“…There is a strong correlation between the extent of TAU hyperphosphorylation and the severity of impairments of memory, speed of mental processing, and executive functions in humans (Augustinack et al, 2002;Ewers et al, 2007;Lace et al, 2009); in experimental animals, learning and memory are impaired when TAU is hyperphosphorylated (Gatz et al, 2006;Kimura et al, 2007).…”

APOE ε4 worsens hippocampal CA1 apical neuropil atrophy and episodic memory

“…AD-related neuropathology itself is subfield-and even strata-selective, affecting the CA1 subfield, including specifically the stratum radiatum/stratum lacunosum-moleculare (CA1-SRLM), before affecting the remainder of the hippocampus. [13][14][15][16][17][18][19] Postmortem measurements of CA1-SRLM synapse loss and atrophy correlated with episodic memory performance before death. 18 Given the central From the Departments of Neurology and Neurological Sciences…”

E-Pharmacophore Model Assisted Discovery of Novel Antagonists of nNOS

“…Recent studies indicate that mitochondrial dysfunction, a pathological feature that can be detected early in AD [3]. Nitric oxide synthases (NOS) are a family of enzymes catalyzing the production of nitric oxide (NO), which functions as neuronal signaling molecule [4]. Altered expression of nNOS by the Aβ stimulus results in the formation of peroxy nitrite and reactive oxygen species [5].…”