(A) Representative micrographs of NeuN stained serial brain sections for 11-month BAC226Q and non-transgenic littermates. (B) Progressive and age-dependent brain weight loss in BAC226Q mice. With the normal development, brain weights of BAC226Q mice is similar to non-transgenic littermates at 2 months (BAC226Q 0.473±0.005 g; Non Tg 0.480±0.010 g, n=3 pairs; p=0.373901). Brain weights of BAC226Q mice were significantly reduced at 11 months (BAC226Q 0.408±0.023 g, Non Tg 0.485±0.035 g, reduced by 15.9%; BAC226Q n=9, Non Tg n=15; p=0.00026), and more severe at 15 months (BAC226Q 0.495±0.013 g, Non Tg 0.341±0.007 g, reduced by 31.0%; n=4 pairs; p=0.00019). (C, D) Striatal atrophy was measured by the Cavalieri stereological estimator. Compared to the non-transgenic littermates, BAC226Q at 2 months had no defects in striatal (BAC226Q 16.556±0.007 mm3, Non Tg 16.167±1.091 mm3; n=3 pairs; p=0.84283) and ventricle volume (BAC226Q 0.345±0.014 mm3, Non Tg 0.351±0.007 mm3; n=3 pairs; p=0.81590). At 11 months, BAC226Q striatal volume was significantly decreased by 34% (BAC226Q 11.789±0.829 mm3, Non Tg 17.765±0.130 mm3; n=4 pairs; p=0.00544) (C), and lateral ventricle volume was increased by 379% (BAC226Q 1.765±0.281 mm3, Non Tg 0.369±0.067 mm3; n=4 pairs; p=0.01270) (D). (E) Total striatal neuron count was estimated by an optical dissector stereological estimator. No significant difference was detected at 2 months (BAC226Q 2,280,000±125,000, Non Tg 2,174,000±127,000; n=3 pairs), but a significant 18% decrease was detected in 11-month BAC226Q (BAC226Q 1,631,000±269,000,, Non Tg 1,988,000±193,000; BAC226Q n=6, Non Tg n=5, p=0.0002). In every subject counted, the estimated coefficient of error was less than 0.1. (F) In 11-month BAC226Q mice striatum, DARPP-32 staining of MSNs was reduced by 18.1% (n=4 pairs, p=0.0012) but no change in 2-month BAC226Q mice striatum. In all panels, Student’s t-test was applied in all analyses. Significance is indicated by ∗=p<0.05, ∗∗=p<0.01 and ∗∗∗=p<0.001.